Spiroindoline modulators of muscarinic receptors

ABSTRACT

The present invention relates to spiroindoline modulators of muscarinic receptors. The present invention also provides compositions comprising such spiroindoline modulators, and methods therewith for treating muscarinic receptor mediated diseases.

CLAIM OF PRIORITY

This application claims the benefit of U.S. provisional application No.60/602,731, filed on Aug. 19, 2004, which is hereby incorporated byreference.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to modulators of muscarinic receptors. Thepresent invention also provides compositions comprising such modulators,and methods therewith for treating muscarinic receptor mediateddiseases.

BACKGROUND OF THE INVENTION

The neurotransmitter acetylcholine binds to two types of cholinergicreceptors: the ionotropic family of nicotinic receptors and themetabotropic family of muscarinic receptors. Muscarinic receptors belongto the large superfamily of plasma membrane-bound G protein coupledreceptors (GPCRs). To date, five subtypes of muscarinic receptors(M₁-M₅) have been cloned and sequenced from a variety of species, andshow a remarkably high degree of homology across species and receptorsubtype. These M₁-M₅ muscarinic receptors are predominantly expressedwithin the parasympathetic nervous system which exerts excitatory andinhibitory control over the central and peripheral tissues andparticipate in a number of physiologic functions, including heart rate,arousal, cognition, sensory processing, and motor control.

Muscarinic agonists such as muscarine and pilocarpine, and antagonists,such as atropine have been known for over a century, but little progresshas been made in the discovery of receptor subtype-selective compounds,thereby making it difficult to assign specific functions to theindividual receptors. See, e.g., DeLapp, N. et al., “TherapeuticOpportunities for Muscarinic Receptors in the Central Nervous System,”J. Med. Chem., 43(23), pp. 4333-4353 (2000); Hulme, E. C. et al.,“Muscarinic Receptor Subtypes,” Ann. Rev. Pharmacol. Toxicol., 30, pp.633-673 (1990); Caulfield, M. P. et al., “MuscarinicReceptors—Characterization, Coupling, and Function,” Pharmacol. Ther.,58, pp. 319-379 (1993); Caulfield, M. P. et al., International Union ofPharmacology. XVII. Classification of Muscarinic AcetylcholineReceptors,” Pharmacol. Rev., 50, pp. 279-290 (1998), the disclosures ofwhich are incorporated herein by reference.

The Muscarinic family of receptors is the target of a large number ofpharmacological agents used for various diseases, including leadingdrugs for COPD, asthma, urinary incontinence, glaucoma, Alzheimer's(AchE inhibitors). Despite the large therapeutic value of this family,cholinergic drugs are limited by the lack of selectivity of theseagents, with significant activation of the parasympathetic autonomoussystem and elevated incidence of adverse effects. The molecular cloningof the muscarinic receptors and the identification of the physiologicalrole of specific isoforms using knock-out mice, has recently delineatednovel opportunities for selective muscarinic ligands, and has helped todefine the selectivity profile that is required for enhanced efficacyand reduced side effects.

There is a need for modulators of muscarinic receptors M₁-M₅. There isalso a need for methods for treating muscarinic receptor-mediateddiseases.

There is also a need for modulators of muscarinic receptors that areselective as to subtypes M₁-M₅.

SUMMARY OF THE INVENTION

The present invention provides methods of modulating activity of amuscarinic receptor using compounds of formula (I):

and pharmaceutically acceptable salts thereof.

Each of R₁, R₂, R₃ is independently Q₁ or Q₂, or R₂ and R₃ together formoxo.

Z₁ is —C(Q₁)₂-, —C(H)(Q₁)-, —C(H)(Q₅)-, —C(O)—, —CH₂—, —N(Q₁)-, —N(Q₂)-,or O.

Z₂ is N.

L is a bond, an aliphatic group, C₃-C₆ cycloaliphatic, —O—, —S(O)_(z)—,—S(O)_(z)—(C₁-C₄)alkyl-, —C(O)N(Q₂)-, or —S(O)_(z) N(Q₂)-, in which thealiphatic group is optionally substituted with 1-3 of oxo, Q₁, or Q₂.

G is a monocycloaliphatic group, a monocycloheteroaliphatic group,adamantyl, or a bicyclic or a tricyclic group of the formula (III)

in which the monocycloaliphatic group, the monocycloheteroalipahticgroup, the adamantyl, and the bicyclic or tricyclic group are connectedto L via any ring atom including those in X₁ and ring B, and themonocycloaliphatic, the monocycloheteroaliphatic, the bicyclic, and thetricyclic groups are optionally substituted with 1-3 of oxo, ═N—OQ₄,fluorine, Q₂, —C(O)—X₂-aliphatic in which X₂ is absent, —O—, —NH—,—NQ₂-, or —S(O)_(z)— and the aliphatic group is optionally substitutedwith 1-3 substituents independently selected from Q₃; bond r is a singleor double bond and when ring B is present, bond r is fused with B; ringB, when present, is a 5-6 membered cycloaliphatic or heterocyclic ring;and ring B is optionally substituted with 1-3 of oxo, Q₁, or Q₂.

X₁ is —(CH₂)_(i)—, —O—, —S—, —N(Q₂)-, —N(C(O)—X₂-aliphatic)- in which X₂is absent, —O—, —NH—, —NQ₂-, or —S(O)_(z)— and the aliphatic group isoptionally substituted with 1-3 substituents independently selected fromQ₃;

Each Q₁ is independently halo, —CN, —NO₂, —OQ₂, —S(O)_(z)Q₂,—S(O)_(z)N(Q₂)₂, —N(Q₂)₂, —C(O)OQ₂, —C(O)-Q₂, —C(O)N(Q₂)₂,—C(O)N(Q₂)(OQ₂), —N(Q₂)C(O)-Q₂, —N(Q₂)C(O)N(Q₂)₂, —N(Q₂)C(O)O-Q₂,—N(Q₂)S(O)_(z)-Q₂ or aliphatic optionally including 1-3 substituentsindependently selected from Q₂ or Q₃.

Each Q₂ is independently H, aliphatic, cycloaliphatic, aryl, arylalkyl,heterocyclic, or heteroaryl ring, each optionally substituted with 1-3substituents independently selected from Q₃.

Each Q₃ is halo, oxo, CN, NO₂, CF₃, OCF₃, OH, —S(O)_(z)Q₄, —N(Q₄)₂,—COOQ₄, —C(O)Q₄, —OQ₄, or C₁-C₄ alkyl optionally substituted with 1-3halo, oxo, —CN, —NO₂, —CF₃, —OCF₃, —OH, —SH, —S(O)_(z)H, —NH₂, or —COOH.

Each Q₄ is aliphatic, cycloaliphatic, aryl, aralkyl,heterocycloaliphatic, heteroaralky, or heteroaryl, each optionallyincluding 1-3 substituents selected from halo, oxo, CN, NO₂, CF₃, OCF₃,OH, SH, —S(O)_(z)H, —NH₂, or COOH.

Each Q₅ is a heterocyclic ring optionally substituted with 1-3substituents selected from halo, C₁-C₄ alkyl, oxo, CN, NO₂, CF₃, OCF₃,OH, SH, —S(O)_(z)H, —NH₂, COOH; and each i is independently 1, 2, or 3;each m and n is independently 1, 2, 3, or 4 provided that m+n is atleast 4; each p is 0 or 1; each y is independently 0 or 1; t is 1 to 4;and each z is independently 0, 1, or 2.

Additional aspects of the present invention provide compounds of formula(II), pharmaceutical compositions that are useful modulators ofmuscarinic receptors, and methods of treating muscarinic receptormediated diseases using compounds of formulae (I and II).

Advantageously, the compounds of the invention are generally selectivefor M₁ and M₄ muscarinic receptors. Unexpectedly, the compounds of theinvention exhibit increased activity and/or efficacy for M₁ and/or M₄muscarinic receptors relative to other muscarinic receptors.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the following definitions shall apply unless otherwiseindicated.

I. Definitions

As used herein, the following definitions shall apply unless otherwiseindicated. For purposes of this invention, the chemical elements areidentified in accordance with the Periodic Table of the Elements, CASversion, Handbook of Chemistry and Physics, 75th Ed. Additionally,general principles of organic chemistry are described in “OrganicChemistry”, Thomas Sorrell, University Science Books, Sausolito: 1999,and “March's Advanced Organic Chemistry”, 5th Ed., Ed.: Smith, M. B. andMarch, J., John Wiley & Sons, New York: 2001, the entire contents ofwhich are hereby incorporated by reference.

The term “muscarinic receptor,” without a prefix specifying the receptorsubtype, refers to one or more of the five receptor subtypes M₁-M₅.

The term “modulating” as used herein means increasing or decreasing,e.g. activity, by a measurable amount. Compounds that modulatemuscarinic activity by increasing the activity of the muscarinicreceptors are called agonists. Compounds that modulate muscarinicactivity by decreasing the activity of the muscarinic receptors arecalled antagonists. An agonist interacts with a muscarinic receptor toincrease the ability of the receptor to transduce an intracellularsignal in response to endogenous ligand binding. An antagonist interactswith a muscarinic receptor and competes with the endogenous ligand(s) orsubstrate(s) for binding site(s) on the receptor to decrease the abilityof the receptor to transduce an intracellular signal in response toendogenous ligand binding.

The phrase “treating or reducing the severity of a muscarinic receptormediated disease” refers both to treatments for diseases that aredirectly caused by muscarinic activities and alleviation of symptoms ofdiseases not directly caused by muscarinic activities. Examples ofdiseases whose symptoms may be affected by muscarinic activity include,but are not limited to, CNS derived pathologies including cognitivedisorders, Attention Deficit Hyperactivity Disorder (ADHD), obesity,Alzheimer's disease, various dementias such as vascular dementia,psychosis including schizophrenia, mania, bipolar disorders, painconditions including acute and chronic syndromes, Huntington's Chorea,Friederich's ataxia, Gilles de la Tourette's Syndrome, Downs Syndrome,Pick disease, clinical depression, Parkinson's disease, peripheraldisorders such as ‘reduction of intra ocular pressure in Glaucoma andtreatment of dry eyes and dry mouth including Sjögren's Syndrome,bradhycardia, gastric acid secretion, asthma, GI disturbances and woundhealing.

As used herein the term “aliphatic’ encompasses the terms alkyl,alkenyl, alkynyl.

As used herein, an “alkyl” group refers to a saturated aliphatichydrocarbon group containing 1-8 (e.g., 1-6 or 1-4) carbon atoms. Analkyl group can be straight or branched. Examples of alkyl groupsinclude, but are not limited to, methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-heptyl, or2-ethylhexyl. An alkyl group can be optionally substituted with one ormore substituents such as halo, cycloalkyl, heterocycloalkyl, aryl,heteroaryl, alkoxy, aroyl, heteroaroyl, alkoxycarbonyl,alkylcarbonyloxy, nitro, cyano, amino, acyl, sulfonyl, sulfinyl,sulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, carbamoyl,cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy,heteroarylalkoxy, or hydroxyl. Without limitation, some examples ofsubstituted alkyls include alkylcarbonylalkyl, carboxyalkyl, cyanoalkyl,hydroxyalkyl, alkoxyalkyl, carbonylalkyl, carboxyalkyl, hydroxyalkyl,oxoalkyl, aralkyl, alkoxyaralkyl, (alkylsulfonylamino)alkyl,(sulfonylamino)alkyl, carbonylaminoalkyl, aminocarbonylalkyl,cycloaliphaticalkyl, cyanoalkyl, aminoalkyl, oxoalkyl,alkoxycarbonylalkyl, (alkoxycarbonylheterocycloalkyl)alkyl,(cycloalkyl)alklyl, (cycloalkenyl)alkyl, (heterocycloalkyl)alkyl, orhaloalkyl.

As used herein, an “alkenyl” group refers to an aliphatic carbon groupthat contains 2-8 (e.g., 2-6 or 2-4) carbon atoms and at least onedouble bond. Like an alkyl group, an alkenyl group can be straight orbranched. Examples of an alkenyl group include, but are not limited to,allyl, isoprenyl, 2-butenyl, and 2-hexenyl. An alkenyl group may beoptionally substituted with one or more substituents such as halo,cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, aroyl,heteroaroyl, alkoxycarbonyl, alkylcarbonyloxy, nitro, cyano, amino,acyl, sulfonyl, sulfinyl, sulfanyl, sulfoxy, urea, thiourea, sulfamoyl,sulfamide, oxo, carbamoyl, cycloalkyloxy, heterocycloalkyloxy, aryloxy,heteroaryloxy, aralkyloxy, heteroarylalkoxy, or hydroxyl.

As used herein, an “alkynyl” group refers to an aliphatic carbon groupthat contains 2-8 (e.g., 2-6 or 2-4) carbon atoms and at least onetriple bond. Like an alkyl group, an alkynyl group can be straight orbranched. An alkynyl group may be optionally substituted with one ormore substituents such as halo, cycloalkyl, heterocycloalkyl, aryl,heteroaryl, alkoxy, aroyl, heteroaroyl, alkoxycarbonyl,alkylcarbonyloxy, nitro, cyano, amino, acyl, sulfonyl, sulfinyl,sulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, carbamoyl,cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy,heteroarylalkoxy, or hydroxyl.

As used herein, an “amino” group refers to —NR^(X)R^(Y) wherein each ofR^(X) and R^(Y) is independently hydrogen, alkyl, cycloalkyl,(cycloalkyl)alkyl, aryl, aralkyl, heterocycloalkyl,(heterocycloalkyl)alkyl, heteroaryl, or carbonyl each of which aredefined herein and are optionally substituted. Examples of amino groupsinclude alkylcarbonylamino, alkylsulfonylamino, alkoxycarbonylamino,(azacycloalkylcarbonyl)amino, heteroaralkylcarbonylamino,heteroarylcarbonylamino, carbonylamino, (heterocycloalkyl)carbonylamino,(heterocycloalkyl)alkylcarbonylamino, heteroarylcarbonylamino,arylcarbonylamino, aralkylcarbonylamino, (cycloalkyl)alkylcarbonylamino,cycloalkylcarbonylamino. When the term “amino” is not the terminal group(e.g., alkylcarbonylamino), it is represented by —NR^(X)—. R^(X) has thesame meaning as defined above. A nonexhaustive list of possible R^(X)and R^(Y) includes sulfonylamino, alkylamino, carbonylamino, carboxy,oxo, hydroxyl, sulfo, mercapto, alkylsulfanyl, alkylsulfinyl,alkylsulfonyl, aminocarbonyl, alkylcarbonyl, cycloalkylcarbonyl,cycloalkylalkylcarbonyl, arylcarbonyl, aralkylcarbonyl,heterocycloalkylcarbonyl, heterocycloalkylalkylcarbonyl,heteroarylcarbonyl, or heteroaralkylcarbonyl.

As used herein, a “carbonyl” group, when used alone or as part ofanother structure refers to —(CO)R^(X), where R^(X) is defined above.When the term “carbonyl” is not the terminal group (e.g.,arylaminoalkylcarbonyl) it is represented by —C(O)R^(X). Withoutlimitation, carbonyl groups can include optionally substitutedaminocarbonyl, alkoxyalkoxycarbonyl, alkylaminocarbonyl, arylcarbonyl(e.g., haloarylcarbonyl), heterocycloalkylcarbonyl,heterocycloalkenylcarbonyl, arylaminocarbonyl (e.g.,haloarylaminocarbonyl), cyanoalkylarylcarbonyl,heterocycloalkoxycarbonyl, alkynyloxycarbonyl, cycloalkoxycarbonyl,heterobicycloarylcarbonyl, alkylheteroarylaminocarbonyl,alkoxyarylcarbonyl (e.g., haloalkoxyarylcarbonyl),(alkylheterocyclo)alkenylcarbonyl, heteroarylcarbonyl, arylcarbonyl,heteroarylcarbonyl, alkoxycarbonyl (e.g., haloalkoxycarbonyl),alkylarylcarbonyl, cycloalkylcarbonyl, alkylheteroarylcarbonyl,arylsulfonylcarbonyl, aminocarbonyl, sulfonylcarbonyl, alkylcarbonyl,alkylsulfonylcarbonyl, alkylcarbonyl, arylaminocarbonyl, or the like. Anonexhaustive list of possible R^(X) and R^(Y) includessulfonylaminocarbonyl, alkylcarbonyl, carbonylamino, carboxy, oxo,hydroxyl, sulfo, mercapto, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl,aminocarbonyl, alkylcarbonyl, cycloalkylcarbonyl,cycloalkylalkylcarbonyl, arylcarbonyl, aralkylcarbonyl,heterocycloalkylcarbonyl, heterocycloalkylalkylcarbonyl,heteroarylcarbonyl, or heteroaralkylcarbonyl.

As used herein, an “aryl” group used alone or as part of a larger moietyas in “aralkyl”, “aralkoxy”, or “aryloxyalkyl” refers to monocyclic(e.g., phenyl); bicyclic (e.g., indenyl, naphthalenyl,tetrahydronaphthyl, tetrahydroindenyl); tricyclic (e.g., fluorenyl,tetrahydrofluorenyl, anthracenyl, or tetrahydroanthracenyl); or abenzofused group having 3 rings. For example, a benzofused groupincludes phenyl fused with two or more C₄₋₈ carbocyclic moieties. Anaryl is optionally substituted with one or more substituents includingaliphatic (e.g., alkyl, alkenyl, or alkynyl); cycloalkyl;(cycloalkyl)alkyl; heterocycloalkyl; (heterocycloalkyl)alkyl; aryl;heteroaryl; alkoxy; cycloalkyloxy; heterocycloalkyloxy; aryloxy;heteroaryloxy; aralkyloxy; heteroaralkyloxy; aroyl; heteroaroyl; amino;aminoalkyl; nitro; carboxy; carbonyl (e.g., alkoxycarbonyl,alkylcarbonyl, aminocarbonyl, (alkylamino)alkylaminocarbonyl,arylaminocarbonyl, heteroarylaminocarbonyl; or sulfonylcarbonyl);aryalkylcarbonyloxy; sulfonyl (e.g., alkylsulfonyl or aminosulfonyl);sulfinyl (e.g., alkylsulfinyl); sulfanyl (e.g., alkylsulfanyl); cyano;halo; hydroxyl; acyl; mercapto; sulfoxy, urea, thiourea, sulfamoyl,sulfamide, oxo, or carbamoyl. Alternatively, an aryl may beunsubstituted.

Examples of substituted aryls include haloaryl, alkoxycarbonylaryl,alkylaminoalkylaminocarbonylaryl, p, m-dihaloaryl,p-amino-p-alkoxycarbonylaryl, m-amino-m-cyanoaryl, aminoaryl,alkylcarbonylaminoaryl, cyanoalkylaryl, alkoxyaryl, aminosulfonylaryl,alkylsulfonylaryl, aminoaryl, p-halo-m-aminoaryl, cyanoaryl,hydroxyalkylaryl, alkoxyalkylaryl, hydroxyaryl, carboxyalkylaryl,dialkylaminoalkylaryl, m-heterocycloaliphatic-o-alkylaryl,heteroarylaminocarbonylaryl, nitroalkylaryl,alkylsulfonylaminoalkylaryl, heterocycloaliphaticcarbonylaryl,alkylsulfonylalkylaryl, cyanoalkylaryl,heterocycloaliphaticcarbonylaryl, alkylcarbonylaminoaryl,hydroxyalkylaryl, alkylcarbonylaryl, aminocarbonylaryl,alkylsulfonylaminoaryl, dialkylaminoaryl, alkylaryl, andtrihaloalkylaryl.

As used herein, an “aralkyl” group refers to an alkyl group (e.g., aC₁₋₄alkyl group) that is substituted with an aryl group. Both “alkyl”and “aryl” are defined herein. An example of an aralkyl group is benzyl.A “heteroaralkyl” group refers to an alkyl group that is substitutedwith a heteroaryl. Both “alkyl” and “heteroaryl” are defined herein.

As used herein, a “bicyclic ring system” includes 8-12 (e.g., 9, 10, or11) membered structures that form two rings, wherein the two rings haveat least one atom in common (e.g., 2 atoms in common). Bicyclic ringstructures include bicycloaliphatics (e.g., bicycloalkyl orbicycloalkenyl), bicycloheteroaliphatics (e.g., bicycloheteroalkyl orbicycloheteroalkenyl), bicyclic aryls, and bicyclic heteroaryls.

The term “cycloaliphatic” means a saturated or partially unsaturatedmonocyclic, bicyclic, or tricyclic hydrocarbon ring that has a singlepoint of attachment to the rest of the molecule. Cycloaliphatic ringsare 3-8 membered monocyclic rings (e.g., 3-6 membered rings).Cycloaliphatic rings also include 8-12 membered bicyclic hydrocarbonrings, (e.g., 10 membered bicyclic hydrocarbon rings). A cycloaliphaticgroup encompasses a “cycloalkyl” group and a “cycloalkenyl” group.

As used herein, a “cycloalkyl” group refers to a saturated carbocyclicmono-, bi-, or tri-, or multicyclic (fused or bridged) ring of 3-10(e.g., 5-10) carbon atoms. Without limitation, examples of monocycliccycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, or the like. Without limitation, examples ofbicyclic cycloalkyl groups include octahydro-indenyl,decahydro-naphthyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl,bicyclo[3.3.1]nonyl, bicyclo[3.3.2.]decyl, bicyclo[2.2.2]octyl,bicycle[2.2.1]heptanyl, bicycle[3.1.1]heptanyl, or the like. Withoutlimitation, multicyclic groups include adamantyl, cubyl, norbornyl, orthe like. Cycloalkyl rings can be optionally substituted at anychemically viable ring position.

A “cycloalkenyl” group, as used herein, refers to a non-aromaticcarbocyclic ring of 3-10 (e.g., 4-8) carbon atoms having one or moredouble bonds. Examples of cycloalkenyl groups include cyclopentenyl,1,4-cyclohexa-di-enyl, cycloheptenyl, cyclooctenyl, hexahydro-indenyl,octahydro-naphthyl, cyclohexenyl, cyclopentenyl, bicyclo[2.2.2]octenyl,and bicyclo[3.3.1]nonenyl. Cycloalkenyl ring structures can beoptionally substituted at any chemically viable position on the ring orrings.

A cycloalkyl or cycloalkenyl group can be optionally substituted withone or more substituents such as aliphatic (e.g., alkyl, alkenyl, oralkynyl), cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl,(heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy,heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy,heteroaralkyloxy, aroyl, heteroaroyl, amino, nitro, carboxy,alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino,cycloalkylcarbonylamino, (cycloalkyl)alkylcarbonylamino,arylcarbonylamino, aralkylcarbonylamino,(heterocycloalkyl)carbonylamino, (heterocycloalkyl)alkylcarbonylamino,heteroarylcarbonylamino, heteroaralkylcarbonylamino, cyano, halo,hydroxyl, acyl, mercapto, sulfonyl (e.g., alkylsulfonyl orarylsulfonyl), sulfinyl (e.g., alkylsulfinyl), sulfanyl (e.g.,alkylsulfanyl), sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo,carbamoyl, or the like.

Without limitation, examples of substituted cycloaliphatics includealkylcycloalkyl (e.g., propylcyclohexyl), alkylbicyclo[3.1.1]heptyl,alkylcycloalkenyl, or the like.

As used herein, the term “heterocycloaliphatic” and “heterocyclic”encompasses a heterocycloalkyl group and a heterocycloalkenyl group.

As used herein, a “heterocycloalkyl” group refers to a 3-10 memberedmono or bicyclic (fused or bridged) (e.g., 5 to 10 membered mono orbicyclic) saturated ring structure, in which one or more of the ringatoms is a heteroatom (e.g., N, O, S, or combinations thereof). Examplesof a heterocycloalkyl group include optionally substituted piperidyl,piperazyl, tetrahydropyranyl, tetrahydrofuryl, 1,4-dioxolanyl,1,4-dithianyl, 1,3-dioxolanyl, oxazolidyl, isoxazolidyl, morpholinyl,thiomorpholyl, octahydro-benzofuryl, octahydro-chromenyl,octahydro-thiochromenyl, octahydro-indolyl, octahydro-pyrindinyl,decahydro-quinolinyl, octahydro-benzo[b]thiopheneyl,2-oxa-bicyclo[2.2.2]octyl, 1-aza-bicyclo[2.2.2]octyl,3-aza-bicyclo[3.2.1]octanyl, 2,6-dioxa-tricyclo[3.3.1.0^(3,7)]nonyl,tropane. A monocyclic heterocycloalkyl group may be fused with a phenylmoiety such as tetrahydroisoquinoline. Heterocycloalkyl ring structurescan be optionally substituted at any chemically viable position on thering or rings.

A “heterocycloalkenyl” group, as used herein, refers to a mono- orbicylic (e.g., 5- to 10-membered mono- or bicyclic) non-aromatic ringstructure having one or more double bonds, and wherein one or more ofthe ring atoms is a heteroatom (e.g., N, O, or S). Examples ofheterocycloalkenyls include 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, or2-pyrazolyl. Monocyclic heteroaliphatics are numbered according tostandard chemical nomenclature. For instance:

A heterocycloalkyl or heterocycloalkenyl group can be optionallysubstituted with one or more substituents such as alkyl (includingcarboxyalkyl, hydroxyalkyl, and haloalkyl such as trifluoromethyl),alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl (suchas a benzimidazolidinyl), (heterocycloalkyl)alkyl, aryl, heteroaryl,alkoxy (two alkoxy groups on the same atom or adjacent atoms may form aring together with the atom(s) to which they are bound), cycloalkyloxy,heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy,heteroaralkyloxy, aroyl, heteroaroyl, amino, nitro, carboxy,alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino,cycloalkylcarbonylamino, (cycloalkyl)alkylcarbonylamino,arylcarbonylamino, aralkylcarbonylamino,(heterocycloalkyl)carbonylamino, (heterocycloalkyl)alkylcarbonylamino,heteroarylcarbonylamino, heteroaralkylcarbonylamino, cyano, halo,hydroxyl, acyl, mercapto, sulfonyl (such as alkylsulfonyl orarylsulfonyl), sulfinyl (such as alkylsulfinyl), sulfanyl (such asalkylsulfanyl), sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, orcarbamoyl.

Without limitation, examples of substituted heterocycloaliphaticsinclude alkoxycarbonylheterocycloalkyl (e.g., ethoxycarbonyltropane),alkoxycarbonylheterocycloalkyl (e.g., ethoxycarbonylpiperidyl), or thelike.

A “heteroaryl” group, as used herein, refers to a monocyclic, bicyclic,or tricyclic ring structure having 4 to 15 ring atoms wherein one ormore of the ring atoms is a heteroatom (e.g., N, O, S, or combinationsthereof) and wherein one or more rings of the bicyclic or tricyclic ringstructure is aromatic. A heteroaryl group includes a benzofused ringsystem having 2 to 3 rings. For example, a benzofused group includesbenzo fused with one or two C₄₋₈ heterocyclic moieties (e.g., indolizyl,indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[b]furyl,benzo[b]thiophenyl, quinolinyl, or isoquinolinyl). Some examples ofheteroaryl are azetidinyl, pyridyl, 1H-indazolyl, furyl, pyrrolyl,thienyl, thiazolyl, oxazolyl, imidazolyl, tetrazolyl, benzofuryl,isoquinolinyl, benzthiazolyl, xanthene, thioxanthene, phenothiazine,dihydroindole, benzo[1,3]dioxole, benzo[b]furyl, benzo[b]thiophenyl,indazolyl, benzimidazolyl, benzthiazolyl, puryl, cinnolyl, quinolyl,quinazolyl, cinnolyl, phthalazyl, quinazolyl, quinoxalyl, isoquinolyl,4H-quinolizyl, benzo-1,2,5-thiadiazolyl, or 1,8-naphthyridyl.

Without limitation, monocyclic heteroaryls include furyl, thiophenyl,2H-pyrrolyl, pyrrolyl, oxazolyl, thazolyl, imidazolyl, pyrazolyl,isoxazolyl, isothiazolyl, 1,3,4-thiadiazolyl, 2H-pyranyl, 4-H-pranyl,pyridyl, pyridazyl, pyrimidyl, pyrazolyl, pyrazyl, or 1,3,5-triazyl.Monocyclic heteroaryls are numbered according to standard chemicalnomenclature. For instance:

Without limitation, bicyclic heteroaryls include indolizyl, indolyl,isoindolyl, 3H-indolyl, indolinyl, benzo[b]furyl, benzo[b]thiophenyl,quinolinyl, isoquimolinyl, indolizyl, isoindolyl, indazolyl,benzimidazyl, benzthiazolyl, purinyl, 4H-quinolizyl, quinolyl,isoquinolyl, cinnolyl, phthalazyl, quinazolyl, quinoxalyl,1,8-naphthyridyl, or pteridyl. Bicyclic heteroaryls are numberedaccording to standard chemical nomenclature. For instance:

A heteroaryl is optionally substituted with one or more substituentssuch as aliphatic including alkyls (e.g., alkoxyalkyl, carboxyalkyl,hydroxyalkyl, oxoalkyl, aralkyl, (alkylsulfonylamino)alkyl,(sulfonylamino)alkyl, cyanoalkyl, aminoalkyl, oxoalkyl,alkoxycarbonylalkyl, (cycloalkyl)alkyl heterocycloalkyl,(heterocycloalkyl)alkyl aralkyl, and haloalkyl such as trifluoromethyl),alkenyl, alkynyl; cycloaliphatic including cycloalkyl (e.g.,cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl);heterocycloaliphatic including hetetocylcoalkyl (e.g., thiomorpholyl,piperazinyl, 1,3,5-trithianyl, morpholinyl, pyrrolyl, 1,3-dioxolanyl,pyrazolidyl, or piperidinyl); aryl, heteroaryl (e.g., quinolyl, indolyl,3H-indolyl, isoindolyl, benzo[b]-4H-pyranyl, cinnolyl, quinoxylyl,benzimidazyl, benzo-1,2,5-thiadiazolyl, benzo-1,2,5-oxadiazolyl, orbenzthiophenyl); alkoxy; cycloalkyloxy; heterocycloalkyloxy; aryloxy;heteroaryloxy; aralkyloxy; heteroaralkyloxy; aroyl; heteroaroyl; amino(e.g., carbonylamino, alkylcarbonylamino, alkylsulfonylamino,arylcarbonylamino, cycloalkylcarbonylamino, arylcarbonylamino,heteroarylcarbonylamino, (heterocycloalkyl)carbonylamino,(cycloalkyl)alkylcarbonylamino, sulfanylamino, and(heterocycloalkyl)alkylcarbonylamino); nitro; carboxy; carbonyl (e.g.,alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, arylaminocarbonyl,thiazoleaminocarbonyl, thiomorpholinecarbonyl, aminoalkylaminocarbonyl);alkylcarbonyloxy; cyano; halo; hydroxyl; acyl; mercapto; sulfonyl (e.g.,aminosulfonyl, alkylsulfonyl, morpholinesulfonyl, or arylsulfonyl);sulfinyl (e.g., alkylsulfinyl); sulfanyl (e.g., alkylsulfanyl); sulfoxy;urea; thiourea; sulfamoyl; sulfamide; oxo; or carbamoyl.

Examples of substituted heteroaryls include haloheteroaryl,alkoxycarbonylheteroaryl, alkylaminoalkylaminocarbonylheteroaryl,dihaloheteroaryl, cyanoheteroaryl, aminoheteroaryl,alkylcarbonylaminoheteroaryl, cyanoalkylheteroaryl, alkoxyheteroaryl,aminosulfonylheteroaryl, alkylsulfonylheteroaryl, aminoheteroaryl,aminoheteroaryl, hydroxyalkylheteroaryl, alkoxyalkylheteroaryl,hydroxyheteroaryl, carboxyalkylheteroaryl, dialkylaminoalkylheteroaryl,heterocycloaliphaticheteroaryl, heteroarylaminocarbonylheteroaryl,nitroalkylheteroaryl, alkylsulfonylaminoalkylheteroaryl,heterocycloaliphaticcarbonylheteroaryl, alkylsulfonylalkylheteroaryl,cyanoalkylheteroaryl, heterocycloaliphaticcarbonylheteroaryl,alkylcarbonylaminoheteroaryl, hydroxyalkylheteroaryl,alkylcarbonylheteroaryl, aminocarbonylheteroaryl,alkylsulfonylaminoheteroaryl, dialkylaminoheteroaryl, alkylheteroaryl,and trihaloalkylheteroaryl.

A “heteroaralkyl” group, as used herein, refers to an alkyl group (e.g.,a C₁₋₄ alkyl group) that is substituted with a heteroaryl group. Both“alkyl” and “heteroaryl” have been defined above.

As used herein, “cyclic moiety” includes cycloalkyl, heterocycloalkyl,cycloalkenyl, heterocycloalkenyl, aryl, or heteroaryl, each of which hasbeen defined previously.

As used herein, an “acyl” group refers to a formyl group or alkyl-C(═O)—(also referred to as “alkylcarbonyl”) where “alkyl” has been definedpreviously. Acetyl and pivaloyl are examples of acyl groups.

As used herein, a “carbamoyl” group refers to a group having thestructure —O—CO—NR^(x)R^(y) or —NR^(x)—CO—O—R^(z) wherein R^(x) andR^(y) have been defined above and R^(z) can be alkyl, aryl, aralkyl,heterocycloalkyl, heteroaryl, or heteroaralkyl.

As used herein, a “carboxy” and a “sulfo” group refer to —COOH or—COOR^(X) and —SO₃H or —SO₃R^(X), respectively.

As used herein, an “alkoxy” group refers to an alkyl-O— group where“alkyl” has been defined previously. Moreover an alkoxy group includesstructures comprising two alkoxy groups on the same atom or adjacentatoms that form a ring together with the atom(s) to which they arebound.

As used herein, a “sulfoxy” group refers to —O—SO—R^(X) or —SO—O—R^(X),where R^(X) has been defined above.

As used herein, a “mercapto” group refers to —SH.

As used herein, a “sulfonyl” group refers to —S(O)₂—R^(X), wherein R^(X)has been defined above. Examples of sulfonyls include optionallysubstituted alkylsulfonyl, arylsulfonyl (e.g., haloarylsulfonyl),heteroarylsulfonyl (e.g., alkylheteroarylsulfonyl), or the like.

As used herein a “sulfinyl” group refers to —S(O)—R^(X), wherein R^(X)has been defined above. Examples of sulfinyls include alkylsulfinyl.

As used herein a “sulfanyl” group refers to —S—R^(X), wherein R^(X) hasbeen defined above. Examples of sulfanyls include alkylsulfanyl.

As used herein, a “halogen” or “halo” group refers to fluorine,chlorine, bromine or iodine.

As used herein, a “haloaliphatic” group refers to an aliphatic groupsubstituted with 1-3 halogen. For instance, the term haloalkyl includesthe group —CF₃.

As used herein, a “sulfamoyl” group refers to the structure—S(O)₂—NR^(x)R^(y) or —NR^(x)—S(O)₂—R^(z) wherein R^(x), R^(y), andR^(z) have been defined above.

As used herein, a “sulfamide” group refers to the structure—NR^(X)—S(O)₂—NR^(Y)R^(Z) wherein R^(X), R^(Y), and R^(Z) have beendefined above.

As used herein, a “carbonylamino” group used alone or in connection withanother group refers to an amido group such as Rx-C(O)—NR^(X)—. Forinstance an alkylcarbonylamino includes alkyl-C(O)—NR^(X)—, whereinR^(X) has been defined above.

As used herein, a “aminocarbonyl” group used alone or in connection withanother group refers to an amido group such as N(Rx)₂-C(O)—.

As used herein, an “alkoxycarbonyl” used alone or in connection withanother group refers to a carbonyl group such as alkyl-O—C(O)—.

As used herein, an “alkoxyalkyl” refers to an alkyl group such asalkyl-O-alkyl-, wherein alkyl has been defined above.

As used herein, an “aminocarbonyl” refers to an amido group such as—NR^(X)—C(O)—, wherein R^(x) has been defined above.

As used herein, an “aminosulfonyl” refers to the structure—N(R^(X))₂—S(O)₂—, wherein R^(x) has been defined above.

As used herein, an “oxo” refers to ═O.

As used herein, an “aminoalkyl” refers to the structure—N(R^(X))₂-alkyl-.

As used herein, a “cyanoalkyl” refers to the structure (CN)-alkyl-.

As used herein, an “alkylsulfonyl’ group refers to the structurealkyl-S(O)₂—.

As used herein, a “sulfonylamino” group refers to the structureRx-S(O)₂—N(R^(X))₂—, wherein R^(x) has been defined above.

As used herein, a “urea” group refers to the structure—NR^(X)—CO—NR^(Y)R^(Z) and a “thiourea” group refers to the structure—NR^(X)—CS—NR^(Y)R^(Z). R^(X), R^(Y), and R^(Z) have been defined above.

In general, the term “substituted,” whether preceded by the term“optionally” or not, refers to the replacement of hydrogen radicals in agiven structure with the radical of a specified substituent. Specificsubstituents are described above in the definitions and below in thedescription of compounds and examples thereof. Unless otherwiseindicated, an optionally substituted group may have a substituent ateach substitutable position of the group, and when more than oneposition in any given structure may be substituted with more than onesubstituent selected from a specified group, the substituent may beeither the same or different at every position. A ring substituent, suchas a heterocycloalkyl, may be bound to another ring, such as acycloalkyl, to form a spiro-bicyclic ring system, e.g., both rings shareone common atom. As one of ordinary skill in the art will recognize,combinations of substituents envisioned by this invention are thosecombinations that result in the formation of stable or chemicallyfeasible compounds.

The phrase “stable or chemically feasible,” as used herein, refers tocompounds that are not substantially altered when subjected toconditions to allow for their production, detection, and preferablytheir recovery, purification, and use for one or more of the purposesdisclosed herein. In some embodiments, a stable compound or chemicallyfeasible compound is one that is not substantially altered when kept ata temperature of 40° C. or less, in the absence of moisture or otherchemically reactive conditions, for at least a week.

As used herein, an effective amount is defined as the amount required toconfer a therapeutic effect on the treated patient, and is typicallydetermined based on age, surface area, weight, and condition of thepatient. The interrelationship of dosages for animals and humans (basedon milligrams per meter squared of body surface) is described byFreireich et al., Cancer Chemother. Rep., 50: 219 (1966). Body surfacearea may be approximately determined from height and weight of thepatient. See, e.g., Scientific Tables, Geigy Pharmaceuticals, Ardsley,N.Y., 537 (1970). As used herein, “patient” refers to a mammal,including a human.

Unless otherwise stated, structures depicted herein are also meant toinclude all isomeric (e.g., enantiomeric, diastereomeric, and geometric(or conformational)) forms of the structure; for example, the R and Sconfigurations for each asymmetric center, (Z) and (E) double bondisomers, and (Z) and (E) conformational isomers. Therefore, singlestereochemical isomers as well as enantiomeric, diastereomeric, andgeometric (or conformational) mixtures of the present compounds arewithin the scope of the invention. Unless otherwise stated, alltautomeric forms of the compounds of the invention are within the scopeof the invention. Additionally, unless otherwise stated, structuresdepicted herein are also meant to include compounds that differ only inthe presence of one or more isotopically enriched atoms. For example,compounds having the present structures except for the replacement ofhydrogen by deuterium or tritium, or the replacement of a carbon by a¹³C— or ¹⁴C-enriched carbon are within the scope of this invention. Suchcompounds are useful, for example, as analytical tools or probes inbiological assays.

II. Compounds

The present invention provides methods of modulating muscarinic receptoractivity using compounds of formulae (I and II), described above, thatare useful in modulating activity of a muscarinic receptor.

Methods of modulating muscarinic receptors according to one aspect ofthe present invention involve compounds of formula (I):

or pharmaceutically acceptable salts thereof.

Each of R₁, R₂, R₃ is independently Q₁ or Q₂, or R₂ and R₃ together formoxo.

Z₁ is —C(Q₁)₂-, —C(H)(Q₁)-, —C(H)(Q₅)-, —C(O)—, —CH₂—, —N(Q₁)-, —N(Q₂)-,or O.

Z₂ is N.

L is a bond, an aliphatic group, C₃-C₆ cycloaliphatic, —O—, —S(O)_(z)—,—S(O)_(z)—(C₁-C₄)alkyl-, —C(O)N(Q₂)-, or —S(O)_(z) N(Q₂)-, in which thealiphatic group is optionally substituted with 1-3 of oxo, Q₁, or Q₂.

G is a monocycloaliphatic group, a monocycloheteroaliphatic group,adamantyl, or a bicyclic or a tricyclic group of the formula (III)

in which the monocycloaliphatic group, the monocycloheteroalipahticgroup, the adamantyl, and the bicyclic or tricyclic group are connectedto L via any ring atom including those in X₁ and ring B, and themonocycloaliphatic, the monocycloheteroaliphatic, the bicyclic, and thetricyclic groups are optionally substituted with 1-3 of oxo, ═N—OQ₄,fluorine, Q₂, —C(O)—X₂-aliphatic in which X₂ is absent, —O—, —NH—,—NQ₂-, or —S(O)_(z)— and the aliphatic group is optionally substitutedwith 1-3 substituents independently selected from Q₃; bond r is a singleor double bond and when ring B is present, bond r is fused with B; ringB, when present, is a 5-6 membered cycloaliphatic or heterocyclic ring;and ring B is optionally substituted with 1-3 of oxo, Q₁, or Q₂.

X₁ is —(CH₂)_(i)—, —O—, —S—, —N(Q₂)-, —N(C(O)—X₂-aliphatic)- in which X₂is absent, —O—, —NH—, —NQ₂-, or —S(O)_(z)— and the aliphatic group isoptionally substituted with 1-3 substituents independently selected fromQ₃.

Each Q₁ is independently halo, —CN, —NO₂, —OQ₂, —S(O)_(z)Q₂,—S(O)_(z)N(Q₂)₂, —N(Q₂)₂, —C(O)OQ₂, —C(O)-Q₂, —C(O)N(Q₂)₂,—C(O)N(Q₂)(OQ₂), —N(Q₂)C(O)-Q₂, —N(Q₂)C(O)N(Q₂)₂, —N(Q₂)C(O)O-Q₂,—N(Q₂)S(O)_(z)-Q₂ or aliphatic optionally including 1-3 substituentsindependently selected from Q₂ or Q₃.

Each Q₂ is independently H, aliphatic, cycloaliphatic, aryl, arylalkyl,heterocyclic, or heteroaryl ring, each optionally including 1-3substituents independently selected from Q₃.

Each Q₃ is halo, oxo, CN, NO₂, CF₃, OCF₃, OH, —S(O)_(z)Q₄, —N(Q₄)₂,—COOQ₄, —C(O)Q₄, —OQ₄, or C₁-C₄ alkyl optionally substituted with 1-3 ofhalo, oxo, —CN, —NO₂, —CF₃, —OCF₃, —OH, —SH, —S(O)_(z)H, —NH₂, or —COOH.

Each Q₄ is aliphatic, cycloaliphatic, aryl, aralkyl, heterocyclic,heteroaralyl, or heteroaryl ring, each optionally substituted with 1-3substituents selected from halo, oxo, CN, NO₂, CF₃, —OCF₃, —OH, —SH,—S(O)_(z)H, —NH₂, —COOH.

Each Q₅ is a heterocyclic ring optionally substituted with 1-3substituents selected from halo, C₁-C₄ alkyl, oxo, CN, NO₂, CF₃, OCF₃,OH, SH, —S(O)_(z)H, —NH₂, COOH; and each i is independently 1, 2, or 3.

Each m and n is independently 1, 2, 3, or 4 provided that m+n is atleast 4.

Each p is 0 or 1.

Each y is independently 0 or 1; each t is 1 to 4; and each z isindependently 0, 1, or 2.

Another aspect of the invention provides compounds of formula (II)including:

or pharmaceutically acceptable salts thereof.

Each of R₁, R₂, R₃ is independently Q₁ or Q₂, or R₂ and R₃ together formoxo.

Z₁ is —C(Q₁)₂-, —C(H)(Q₁)-, —C(H)(Q₅)-, —C(O)—, —CH₂—, —N(Q₁)-, —N(Q₂)-,or O.

Z₂ is N.

L is a bond, an aliphatic group, C₃-C₆ cycloaliphatic, —O—, —S(O)—,—S(O)_(z)—(C₁-C₄)alkyl-, —C(O)N(Q₂)-, or —S(O)_(z) N(Q₂)-, in which thealiphatic group is optionally substituted with 1-3 of oxo, Q₁, or Q₂.

G is a monocycloaliphatic group, a monocycloheteroaliphatic group,adamantyl, or a bicyclic or a tricyclic group of formula (III)

in which the monocycloaliphatic group, the monocycloheteroaliphaticgroup, the adamantyl, and the bicyclic or tricyclic group are connectedto L via any ring atom including those in X₁ and ring B, and themonocycloaliphatic, the monocycloheteroaliphatic, the bicyclic, and thetricyclic groups are optionally substituted with 1-3 of oxo, ═N—OQ₄,fluorine, Q₂, —C(O)—X₂-aliphatic in which X₂ is absent, —O—, —NH—,—NQ₂-, or —S(O)_(z)— and the aliphatic group is optionally substitutedwith 1-3 substituents independently selected from Q₃; bond r is a singleor double bond and when ring B is present, bond r is fused with B; ringB, when present, is a 5-6 membered cycloaliphatic or heterocyclic ring,and is optionally substituted with 1-3 of oxo, Q₁, or Q₂.

X₁ is —(CH₂)_(i)—, —O—, —S—, —N(Q₂)-, —N(C(O)—X₂-aliphatic)- in which X₂is absent, —O—, —NH—, —NQ₂-, or —S(O)_(z)— and the aliphatic group isoptionally substituted with 1-3 substituents independently selected fromQ₃.

Each Q₁ is independently halo, —CN, —NO₂, —OQ₂, —S(O)_(z)Q₂,—S(O)_(z)N(Q₂)₂, —N(Q₂)₂, —C(O)OQ₂, —C(O)-Q₂, —C(O)N(Q₂)₂,—C(O)N(Q₂)(OQ₂), —N(Q₂)C(O)-Q₂, —N(Q₂)C(O)N(Q₂)₂, —N(Q₂)C(O)O-Q₂,—N(Q₂)S(O)_(z)-Q₂ or aliphatic optionally including 1-3 substituentsindependently selected from Q₂ or Q₃.

Each Q₂ is independently H, aliphatic, cycloaliphatic, aryl, arylalkyl,heterocyclic, or heteroaryl ring, each optionally substituted with 1-3substituents independently selected from Q₃.

Each Q₃ is halo, oxo, —CN, —NO₂, —CF₃, —OCF₃, —OH, —S(O)_(z)Q₄, —N(Q₄)₂,—COOQ₄, —C(O)Q₄, —OQ₄, or C₁-C₄ alkyl optionally substituted with 1-3halo, oxo, —CN, —NO₂, —CF₃, —OCF₃, —OH, —SH, —S(O)_(z)H, —NH₂, or —COOH.

Each Q₄ is aliphatic, cycloaliphatic, aryl, aralkyl,heterocycloaliphatic, heteroaralky, or heteroaryl, each optionallyincluding 1-3 substituents selected from halo, oxo, CN, NO₂, CF₃, OCF₃,OH, SH, —S(O)_(z)H, —NH₂, or COOH.

Each Q₅ is a heterocyclic ring optionally substituted with 1-3substituents selected from halo, oxo, C₁-C₄alkyl, —CN, —NO₂, —CF₃,—OCF₃, —OH, —SH, —S(O)_(z)H, —NH₂, and —COOH.

Each i is independently 1, 2, or 3.

Each p is 0 or 1.

Each y is independently 0 or 1.

Each z is independently 0, 1, or 2.

III. Specific Embodiments

a. Substituent G

G is a monocycloaliphatic group, a monocycloheteroaliphatic group,adamantyl, or a bicyclic or a tricyclic group of formula (III)

in which the monocycloaliphatic group, the monocycloheteroaliphaticgroup, the adamantyl, and the bicyclic or tricyclic group are connectedto L via any ring atom including those in X₁ and ring B, and themonocycloaliphatic, the monocycloheteroaliphatic, the bicyclic, and thetricyclic groups are optionally substituted with 1-3 of oxo, ═N—OQ₄,fluorine, Q₂, —C(O)—X₂-aliphatic in which X₂ is absent, —O—, —NH—,—NQ₂-, or —S(O)_(z)— and the aliphatic group is optionally substitutedwith 1-3 substituents independently selected from Q₃; bond r is a singleor double bond and when ring B is present, bond r is fused with B; ringB, when present, is a 5-6 membered cycloaliphatic or heterocyclic ring,and is optionally substituted with 1-3 of oxo, Q₁, or Q₂.

In certain embodiments, G is an optionally substitutedmonocycloaliphatic group.

In several embodiments, G is an optionally substituted cycloaliphatic.In examples of this embodiment, G is an optionally substitutedmonocycloaliphatic. Specific examples of G include, but are not limitedto, 5 to 8 membered monocycloalkyls or a 5 to 8 memberedmonocycloalkenyls. In other examples, G can be an optionally substitutedcyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, orcyclooctyl.

In several embodiments, G is optionally substituted with Q₂, or—C(O)—X₂-aliphatic, where X₂ is absent, —O—, —NH—, or —NQ₂-, and thealiphatic group is optionally substituted with 1-3 substituentsindependently selected from Q₃. In examples of these embodiments, G canbe substituted with carbonyl, sulfonyl, alkoxy, combinations thereof, orthe like.

In several embodiments, G is optionally substituted with 1 to 3 ofcarbonyl, sulfonyl, or combinations thereof. Examples of G include, butare not limited to, alkoxycarbonyl, aliphaticcarbonyl (e.g.,alkylcarbonyl, alkenylcarbonyl, or alkynylcarbonyl), aliphatic,alkoxyalkoxycarbonyl, cycloalkoxycarbonyl, heterocycloalkoxycarbonyl,aminoaliphatic, aliphaticamino, arylcarbonyl, or heteroarylcarbonyl,each of which is optionally substituted.

In several embodiments, G is substituted with alkyl, aryl, haloalkyl,alkoxycarbonyl, or alkoxyamino.

In several embodiments, G is selected from

In several embodiments, G is an optionally substitutedmonoheterocycloaliphatic group. Examples of G include, but are notlimited to, optionally substituted 5 to 7 memberedmonoheterocycloaliphatic groups.

In several embodiments, G includes at least 1 nitrogen atom. G can besubstituted with 1 to 3 substituents independently selected from Q₂, and—C(O)—X₂-aliphatic, where X₂ is absent, —O—, —NH—, or —NQ₂-, and thealiphatic group is optionally substituted with 1-3 substituentsindependently selected from Q₃.

In several embodiments, G is optionally substituted with 1 to 2substituents independently selected from alkoxycarbonyl,alkynyloxycarbonyl, alkoxyalkoxycarbonyl, haloalkoxycarbonyl,heterocycloalkoxycarbonyl, and cycloalkoxycarbonyl.

In other embodiments, G is one selected from

In several embodiments, G includes at least one O atom. In severalexamples, G is optionally substituted with 1 to 3 substituentsindependently selected from independently selected from alkoxycarbonyl,alkynyloxycarbonyl, alkoxyalkoxycarbonyl, haloalkoxycarbonyl,heterocycloalkoxycarbonyl, and cycloalkoxycarbonyl. In other examples, Gis unsubstituted.

In several embodiments, G is one selected from

In other embodiments, G is an optionally substituted bicyclic group offormula (III). In one group of examples, ring B is absent from thebicyclic group of formula (III).

In several embodiments, X₁ is —(CH)_(2i)—.

In several alternative embodiments, the bicyclic group of formula (III)includes 7 to 9 ring atoms. In specific examples, G is an optionallysubstituted bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl,bicyclo[3.3.1]nonyl, bicyclo[2.2.2]octyl, or bicyclo[2.2.1]heptanyl. Inyet another group of the examples, G can be substituted with 1 to 3substituents independently selected from Q₂, and —C(O)—X₂-aliphatic,where X₂ is absent, —O—, —NH—, or —NQ₂-, and the aliphatic group isoptionally substituted with 1-3 substituents independently selected fromQ₃.

In several embodiments, G is one selected from

In other embodiments, G is optionally substituted adamantly.

In several embodiments, X₁ is —N(Q₂)- or —N(C(O)—X₂-aliphatic), where X₂is absent, —O—, —NH—, or —NQ₂-, and the aliphatic group is optionallysubstituted with 1-3 substituents independently selected from Q₃. In onegroup of examples, G is an optionally substituted tropane.

In other examples, G is substituted with Q₂, and —C(O)—X₂-aliphatic,where X₂ is absent, —O—, —NH—, or —NQ₂-, and the aliphatic group isoptionally substituted with 1-3 substituents independently selected fromQ₃.

In several embodiments, G is substituted with alkoxycarbonyl,alkoxyalkoxycarbonyl, heterocycloalkoxycarbonyl, cycloalkoxycarbonyl,alkoxyaryloxycarbonyl, alkylaminocarbonyl, haloalkoxycarbonyl,alkynyloxycarbonyl, or heterocycloalkylalkoxycarbonyl.

In several embodiments, G is one selected from

Z₁ is —C(Q₁)₂-, —C(H)(Q₁)-, —C(H)(Q₅)-, —C(O)—, —CH₂—, —N(Q₁)-, —N(Q₂)-,or O.

In several embodiments, Z₁ is optionally substituted carbon or nitrogenatom. In one group of examples, Z₁ is substituted with amino,alkylcarbonylamino, alkylsulfonylamino, alkoxycarbonylamino,aminocarbonyl, alkylcarbonylalkyl, alkoxyalkoxycarbonyl, alkoxyalkyl,alkylaminocarbonyl, alkoxycarbonyl, haloarylcarbonyl, haloarylsulfonyl,alkylheteroarylcarbonyl, heteroarylcarbonyl, heterocycloalkylcarbonyl,haloarylaminocarbonyl, alkylheteroarylsulfonyl, cyanoalkylarylcarbonyl,heterocycloalkoxycarbonyl, alkynyloxycarbonyl, cycloalkoxycarbonyl,heterobicycloarylcarbonyl, alkylheteroarylaminocarbonyl, alkylsulfonyl,alkylcarbonylalkyl, alkoxyarylcarbonyl, haloalkoxycarbonyl,alkylarylcarbonyl, haloalkoxyarylcarbonyl, or arylaminocarbonyl.

In several embodiments, Z₁ is one selected from

c. Substituents R₁, R₂, and R₃

Each of R₁, R₂, R₃ is independently Q₁ or Q₂, or R₂ and R₃ together formoxo.

In several embodiments, R₁ is hydrogen, halo, or optionally substitutedalkyl, heteroaryl, alkoxy, alkenyl, cycloalkyl, cyanoalkylaryl,alkylaryl, alkylsulfonylaryl, alkylcarbonylaryl, aryl,aminocarbonylaryl, alkylcarbonylaminoaryl, cycloalkenyl, or alkoxyaryl.R₁ groups can be optionally substituted with 1 to 3 substituentsselected from amino, carbonyl, alkoxycarbonyl, aminocarbonyl, aryl,aliphatic, alkoxy, and sulfonyl.

In other embodiments, R₁ is one selected from hydrogen, halo, methyl,—OCH₃,

In several embodiments, R₂ and R₃ are independently hydrogen, alkyl,arylalkyl, or R₂ and R₃ together form an oxo or amino.

In still other embodiments, R₂ and R₃ are independently hydrogen, alkyl,or R₂ and R₃ together form an oxo.

d. L Groups

L is a bond, an aliphatic group, C₃-C₆ cycloaliphatic, —O—, —S(O)_(z)—,—S(O)_(z)—(C₁-C₄)alkyl-, —C(O)N(Q₂)-, or —S(O)_(z) N(Q₂)-, in which thealiphatic group is optionally substituted with 1-3 of oxo, Q₁, or Q₂. Insome embodiments, L is a bond or an aliphatic group in which thealiphatic group is optionally substituted with 1-3 of oxo, Q₁, or Q₂. Inother embodiments, L is a bond. In still further embodiments, L is analiphatic group optionally substituted with 1-3 of oxo, Q₁, or Q₂. L isCH₂.

e. Combinations of Embodiments

Other embodiments include any combination of the aforementionedsubstituents G, Z₁, L, R₁, R₂, and R₃.

f. Excluded Compounds

In several embodiments, when Z₁ is —CH₂— or —N(CH₃)—, L is a bond, and Gis an optionally substituted monocycloaliphatic, an optionallysubstituted monocycloheteroalipahtic group, or a norbornanyl group, thenthe R₁ substituent on the indane or indole is other than H.

In several embodiments, when L is —C(O)—CH₂— and Z₁ is —N(Q₁)-, and Q₁on Z₁ is —S(O)₂-optionally substituted phenyl, then the R₁ substituenton the indole is other than H.

In several embodiments, when L is —S(O)₂—(C₁-C₄)alkyl-, Z₁ is —CH₂—,then the R₁ substituent on the indane or tetrahydronaphthyl is otherthan H.

In several embodiments, when L is —S(O)₂—(C₁-C₄)alkyl-, R₂ and R₃ form═O, Z₁ is —N(Q₁)-, and Q₁ is aliphatic or —S(O)₂-aliphatic, then the R₁substituent on the indole is other than H.

In several embodiments, when L is aliphatic, and R₂ and R₃ form ═O, andZ₁ is —N(Q₁)-, Q₁ is aliphatic, G is a substitutedmonocycloheteroaliphatic group, then the R₁ substituent on the indole isother than H.

In certain embodiments, L is not —S(O)₂—(C₁-C₄)alkyl-.

g. Specific Embodiments

Specific compounds of formulae (I or II) are shown below. Compounds1-120 and 122-430 share the core structure of formula II.

TABLE 1 Specific Compounds 1

2

3

4

5

6

7

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IV. Synthetic Schemes

The compounds of formulae (I and II) may be readily synthesized fromcommercially available starting materials using methods known in theart. Exemplary synthetic routes to produce compounds of formulae (I andII), are provided below in Preparations A-F and Schemes 1-10. Forsimplicity of illustration, schemes 1-10 depict only a single R₁substituent on the fused phenyl ring of formulae I and II, the compoundsof this invention may include 1 to 4 R₁ substituents on the fused phenylring.

Scheme 1 below depicts general conditions for the synthesis of compoundsof formula (I).

The reaction of amine (A) with an appropriate aldehyde or ketone underreductive amination conditions (step a), typically using NaBH(OAc)₃ inDCE/AcOH/TEA at room temperature, may be used to provide the desiredcompounds of formula I. For less reactive ketones, more forcingconditions may be used. For example, the treatment of the amine (A) andthe ketone in a neat solution of Ti(OiPr)₄, followed by treatment withNaBH₄ in MeOH, may be used to provide the desired compounds of formulaI. See Abdel-Magid, A. F. et al., “Reductive Amination of Aldehydes andKetones with Sodium Triacetoxyborohydride. Studies on Direct andIndirect Reductive Amination Procedures,” J. Org. Chem., 61, pp.3849-3862 (1996) and the references sited therein.

Alternatively, the of spiroamine of type A may be alkylated with analkyl halide in the presence of an appropriate base to provide thedesired compounds of formula I. Typically, the amine (A) is reacted withan alkyl iodide, bromide, or chloride in the presence of an appropriatebase to yield compounds of formula I. Bases may be organic such astriethylamine, or inorganic such as Na₂CO₃ or Cs₂CO₃. Typical reactionsolvents include but are not limited to DMF, acetone, and acetonitrile.

Scheme 2 illustrates alternative conditions for the synthesis ofcompounds of formula I in which Z₁ is —C(H)₂— and R₂ and R₃ are hydrogen(Synthetic route A), or in which Z₁ is —C(O)— (Synthetic route B).

Compounds of type i in Scheme 2 may be prepared using procedures asdescribed in Evans, B. E, et al., J. Med. Chem. 1992, 35, 3919 and M. S.Chambers J. Med. Chem. 1992, 35, 2033. Intermediate compounds may beproduced from compound of type i using the following conditions: (a)KMnO₄ oxidation, TBAB, aqueous KOH (b) NaH, X—R₂ and/or X—R₃, THF (c)Ammonium formate, MeOH, Pd/C, room temperature or heat; or Pd/C, MeOH,H₂; or if PG=Boc, then TFA, CH₂Cl₂, −10° C.; (d) NaBH(OAc)₃, DCE, AcOH,TEA, appropriate ketone or aldehyde; or i. neat Ti(OiPr)₄, appropriateketone; ii. NaBH₄, MeOH; or the appropriate alkyl halide, Cs₂CO₃,acetonitrile, heat.

Scheme 3 illustrates alternative conditions for the synthesis ofcompounds of formula I in which Z₁ is —O— and R₂ and R₃ are hydrogen.

Amines of type iv in Scheme 3 were prepared using procedures analogousto those found in the following references: WO 96/11934 “Tricyclic spirocompounds process for their preparation” and US 006013652A“Spiro-substituted azacyclics as neurokinin antagonists”. Conditions:(a) Ph₃P/DEAD (b) Bu₃SnH, AIBN (c) Ammonium formate, MeOH, Pd/C, roomtemperature or heat; or Pd/C, MeOH, H₂; or if PG=Boc, then TFA, CH₂Cl₂,−10° C.; (d) NaBH(OAc)₃, DCE, AcOH, TEA, appropriate ketone or aldehyde;or i. neat Ti(OiPr)₄, appropriate ketone; ii. NaBH₄, MeOH; or theappropriate alkyl halide, Cs₂CO₃, acetonitrile, heat.

Scheme 4 illustrates alternative conditions for the synthesis ofcompounds of formula I in which Z₁ is —N(Q1)- and R₂ and R₃ arehydrogen.

Amines of type i in Scheme 4 may be prepared from methods known in theart and by using procedures analogous to those found in the followingreferences: WO 03/106457 “Spiroindolinepiperidine Derivatives”;Maligres, P. E., et al., Tetrahedron, 1997, 53, 10983-10992; Cheng, Y.and Chapman, K. T., Tet. Lett. 1997, 38, 1497-1500; US006013652A“Spiro-substituted azacyclics as neurokinin antagonists”. Conditions:(a) amine protection orthoganol to PG₁; (b) amine deprotection of PG₁(e.g. PG₁=Boc: TFA, CH₂Cl₂, −10° C.); (c) NaBH(OAc)₃, DCE, AcOH, TEA,appropriate ketone or aldehyde; or i. neat Ti(OiPr)₄, appropriateketone; ii. NaBH₄, MeOH; or the appropriate alkyl halide, Cs₂CO₃,acetonitrile, heat; (d) Q₂X (Q₂ may be, for example, H and aliphatic, Xis halogen), K₂CO₃, DMF/THF, RT to 60° C.; or electrophile (e.g. RSO₂Cl,RCOCl, ROC(═O)Cl, where R is H or Q₂, TEA, CH₃CN.

Reaction of i with intermediate under palladium cross couplingconditions (step a) Pd(dppf)Cl2 or (Ph₃P)₄Pd, 2M K₂CO₃, and acetonitrileunder microwave irradiation at 150° C. for 10-20 minutes yields compoundii. Unsaturated compounds of type ii may be further elaborated (e.g.reduction; oxidation) to provide additional compounds of formula (I).

Scheme 6 illustrates alternative conditions for the synthesis ofcompounds of formula I in which Z₁ is —N(Q₁)- or —N(Q₂)-, R₂ and R₃together form oxo, and p=1.

Compound i may be produced by methods disclosed above and by those knownin the art. Intermediate compounds may be produced from compounds oftype i using the following conditions: (a) NH₂OH.HCl; (b)2,4,6-trichloro-1,3,5-triazine; (c) PG=Bn or Cbz; Ammonium formate,MeOH, Pd/C, room temperature; or Pd/C, MeOH, H₂; (d) NaBH(OAc)₃, DCE,AcOH, TEA, appropriate ketone or aldehyde; or i. neat Ti(OiPr)₄,appropriate ketone; ii. NaBH₄, MeOH; or the appropriate alkyl halide,Cs₂CO₃, acetonitrile, heat; (e) optional alkylation, NaH, THF,appropriate alkyl halide.

Scheme 7 illustrates alternative conditions for the synthesis ofcompounds of formula I in which Z₁ is —CH(Q₁)- and R₂ and R₃ arehydrogen.

Compound i may be produced by methods disclosed above and by those knownin the art. Compounds ii through ix may be produced from compound iusing the following conditions: (a) ZnCl₂ or other Lewis acid, (R)- or(S)-1-phenylethanamine, PhCH₃ reflux, Dean-Stark; (b) NaBH₄, MeOH, −30°C.; (c) Q₂′X (Q₂′ may be, for example, H and aliphatic, X is halogen),K₂CO₃, DMF/THF, RT to 60° C. (d) Ammonium formate, MeOH, Pd/C, roomtemperature; or Pd/C, MeOH, H₂; (e) electrophile (e.g. RSO₂Cl, RCOCl,ROC(═O)Cl, where R is H or alkyl, and Q₂″ is RSO₂—, RC(O)—, ROC(O)—,TEA, CH₃CN; (f) PG=Boc: TFA, CH₂Cl₂, −10° C.; (g) NaBH(OAc)₃, DCE, AcOH,TEA, appropriate ketone or aldehyde; or i. neat Ti(OiPr)₄, appropriateketone; ii. NaBH₄, MeOH; or the appropriate alkyl halide, Cs₂CO₃,acetonitrile, heat.

Scheme 8 illustrates alternative conditions as example for the synthesisof compounds of formula I in which Ring G contains or is substitutedwith a protected functionality which may be either be retained,deprotected and retained, or deprotected and further elaborated toproduce additional compounds of formula I.

Compound i may be produced by methods disclosed above and by those knownin the art. Compounds ii through iv may be produced from compound iusing the following conditions: (a) e.g. PG=ketal: AcOH/H₂O, heat;PG=Boc: TFA, CH₂Cl₂; (b) e.g. if ring G is substituted by oxo, thecompound of formula I may be further elaborated to the oxime: NH₂—O-Q₂,pyridine; (c) e.g. if ring G contains or is substituted by —NH— or—N(Q₂)-, it may be elaborated with an appropriate electrophile toproduce iv.

Scheme 9 illustrates alternative conditions for the synthesis ofcompounds of formula I in which Z₁ is —N(Q₁)- or —N(Q₂)-, and R₂ and R₃are oxo, and p=0.

Compounds of type i may be purchased commercially or produced by methodsknown in the art. Conditions: (a) NaH/HMDS/THF; (b) e.g. PG=Bn: Pd(OH)₂;(c) NaBH(OAc)₃, DCE, AcOH, TEA, appropriate ketone or aldehyde; or i.neat Ti(OiPr)₄, appropriate ketone; ii. NaBH₄, MeOH; or the appropriatealkyl halide, Cs₂CO₃, acetonitrile, heat.

Scheme 10 outlines the general preparation of the appropriate aldehydesfrom the corresponding ketone.

Ketone electrophiles of type i may be purchased commercially or producedby methods disclosed above and by those known in the art. Aldehydes oftype ii may be purchased commercially or produced from compounds of typei using the following conditions: (a) Ph₃P⁺CH₂OMeCl⁻, NaN(SiMe₃)₂; (b)aqueous HCl, CH₃CN. The following conditions may be used for thesynthesis of compounds of formula I using ketones of type i andaldehydes of type ii: (c) Spiro-amine of type A (see Scheme 1),NaBH(OAc)₃, DCE, AcOH, TEA, appropriate ketone or aldehyde; or i. neatTi(OiPr)₄, appropriate ketone; ii. NaBH₄, MeOH.

V. Formulations, Administrations, and Uses

The present invention includes within its scope pharmaceuticallyacceptable prodrugs of the compounds of the present invention. A“pharmaceutically acceptable prodrug” means any pharmaceuticallyacceptable salt, ester, salt of an ester, or other derivative of acompound of the present invention which, upon administration to arecipient, is capable of providing (directly or indirectly) a compoundof this invention or an active metabolite or residue thereof. Preferredprodrugs are those that increase the bioavailability of the compounds ofthis invention when such compounds are administered to a mammal or whichenhance delivery of the parent compound to a biological compartmentrelative to the parent species.

The term “pharmaceutically acceptable carrier, adjuvant, or vehicle”refers to a non-toxic carrier, adjuvant, or vehicle that does notdestroy the pharmacological activity of the compound with which it isformulated. Pharmaceutically acceptable carriers, adjuvants or vehiclesthat may be used in the compositions of this invention include, but arenot limited to, ion exchangers, alumina, aluminum stearate, lecithin,serum proteins, such as human serum albumin, buffer substances such asphosphates, glycine, sorbic acid, potassium sorbate, partial glyceridemixtures of saturated vegetable fatty acids, water, salts orelectrolytes, such as protamine sulfate, disodium hydrogen phosphate,potassium hydrogen phosphate, sodium chloride, zinc salts, colloidalsilica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-basedsubstances, polyethylene glycol, sodium carboxymethylcellulose,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers,polyethylene glycol and wool fat.

Pharmaceutically acceptable salts of the compounds of this inventioninclude those derived from pharmaceutically acceptable inorganic andorganic acids and bases. Examples of suitable acid salts includeacetate, adipate, alginate, aspartate, benzoate, benzenesulfonate,bisulfate, butyrate, citrate, camphorate, camphorsulfonate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptanoate, glycerophosphate, glycolate,hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, malonate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate,palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, salicylate, succinate, sulfate, tartrate,thiocyanate, tosylate and undecanoate. Other acids, such as oxalic,while not in themselves pharmaceutically acceptable, may be employed inthe preparation of salts useful as intermediates in obtaining thecompounds of the invention and their pharmaceutically acceptable acidaddition salts.

Salts derived from appropriate bases include alkali metal (e.g., sodiumand potassium), alkaline earth metal (e.g., magnesium), ammonium andN⁺(C₁₋₄ alkyl)₄ salts. This invention also envisions the quaternizationof any basic nitrogen-containing groups of the compounds disclosedherein. Water or oil-soluble or dispersible products may be obtained bysuch quaternization.

The compositions of the present invention may be administered orally,parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir. The term “parenteral”as used herein includes subcutaneous, intravenous, intramuscular,intra-articular, intra-synovial, intrasternal, intrathecal,intrahepatic, intralesional and intracranial injection or infusiontechniques. Preferably, the compositions are administered orally,intraperitoneally or intravenously. Sterile injectable forms of thecompositions of this invention may be aqueous or oleaginous suspension.These suspensions may be formulated according to techniques known in theart using suitable dispersing or wetting agents and suspending agents.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally-acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium.

For this purpose, any bland fixed oil may be employed includingsynthetic mono- or di-glycerides. Fatty acids, such as oleic acid andits glyceride derivatives are useful in the preparation of injectables,as are natural pharmaceutically-acceptable oils, such as olive oil orcastor oil, especially in their polyoxyethylated versions. These oilsolutions or suspensions may also contain a long-chain alcohol diluentor dispersant, such as carboxymethyl cellulose or similar dispersingagents that are commonly used in the formulation of pharmaceuticallyacceptable dosage forms including emulsions and suspensions. Othercommonly used surfactants, such as Tweens, Spans and other emulsifyingagents or bioavailability enhancers which are commonly used in themanufacture of pharmaceutically acceptable solid, liquid, or otherdosage forms may also be used for the purposes of formulation.

The pharmaceutically acceptable compositions of this invention may beorally administered in any orally acceptable dosage form including, butnot limited to, capsules, tablets, aqueous suspensions or solutions. Inthe case of tablets for oral use, carriers commonly used include lactoseand corn starch. Lubricating agents, such as magnesium stearate, arealso typically added. For oral administration in a capsule form, usefuldiluents include lactose and dried cornstarch. When aqueous suspensionsare required for oral use, the active ingredient is combined withemulsifying and suspending agents. If desired, certain sweetening,flavoring or coloring agents may also be added.

Alternatively, the pharmaceutically acceptable compositions of thisinvention may be administered in the form of suppositories for rectaladministration. These can be prepared by mixing the agent with asuitable non-irritating excipient that is solid at room temperature butliquid at rectal temperature and therefore will melt in the rectum torelease the drug. Such materials include cocoa butter, beeswax andpolyethylene glycols.

The pharmaceutically acceptable compositions of this invention may alsobe administered topically, especially when the target of treatmentincludes areas or organs readily accessible by topical application,including diseases of the eye, the skin, or the lower intestinal tract.Suitable topical formulations are readily prepared for each of theseareas or organs.

Topical application for the lower intestinal tract can be effected in arectal suppository formulation (see above) or in a suitable enemaformulation. Topically-transdermal patches may also be used.

For topical applications, the pharmaceutically acceptable compositionsmay be formulated in a suitable ointment containing the active componentsuspended or dissolved in one or more carriers. Carriers for topicaladministration of the compounds of this invention include, but are notlimited to, mineral oil, liquid petrolatum, white petrolatum, propyleneglycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax andwater. Alternatively, the pharmaceutically acceptable compositions canbe formulated in a suitable lotion or cream containing the activecomponents suspended or dissolved in one or more pharmaceuticallyacceptable carriers. Suitable carriers include, but are not limited to,mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax,cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

For ophthalmic use, the pharmaceutically acceptable compositions may beformulated as micronized suspensions in isotonic, pH adjusted sterilesaline, or, preferably, as solutions in isotonic, pH adjusted sterilesaline, either with or without a preservative such as benzylalkoniumchloride. Alternatively, for ophthalmic uses, the pharmaceuticallyacceptable compositions may be formulated in an ointment such aspetrolatum.

The pharmaceutically acceptable compositions of this invention may alsobe administered by nasal aerosol or inhalation. Such compositions areprepared according to techniques well-known in the art of pharmaceuticalformulation and may be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, fluorocarbons, and/or other conventional solubilizingor dispersing agents.

Most preferably, the pharmaceutically acceptable compositions of thisinvention are formulated for oral administration.

The amount of the compounds of the present invention that may becombined with the carrier materials to produce a composition in a singledosage form will vary depending upon the host treated, the particularmode of administration. Preferably, the compositions should beformulated so that a dosage of between 0.01-100 mg/kg body weight/day ofthe modulator can be administered to a patient receiving thesecompositions.

It should also be understood that a specific dosage and treatmentregimen for any particular patient will depend upon a variety offactors, including the activity of the specific compound employed, theage, body weight, general health, sex, diet, time of administration,rate of excretion, drug combination, and the judgment of the treatingphysician and the severity of the particular disease being treated. Theamount of a compound of the present invention in the composition willalso depend upon the particular compound in the composition.

Depending upon the particular condition, or disease, to be treated orprevented, additional therapeutic agents, which are normallyadministered to treat or prevent that condition, may also be present inthe compositions of this invention. As used herein, additionaltherapeutic agents that are normally administered to treat or prevent aparticular disease, or condition, are known as “appropriate for thedisease, or condition, being treated.”

According to a preferred embodiment, the compounds of formulae (I andII) are selective modulators of M₁, M₂ and M₄. More preferably, thecompounds of formulae (I and II) are selective modulators of M₁ and/orM₄. Yet more preferably, certain compounds of formulae (I and II) areselective modulators of M₁. Or, preferably, certain compounds offormulae (I and II) are selective modulators of M₄.

Applicants believe that the ability of the compounds of the presentinvention to modulate the activity of muscarinic receptors is derivedfrom the affinity of these compounds to the muscarinic receptors. Suchaffinity, applicants believe, activates a muscarinic receptor (i.e., anagonist) or inhibits the activity of a muscarinic receptor.

The term “selective” as used herein means a measurably greater abilityto modulate one muscarinic receptor subtype when compared to the othermuscarinic receptor subtypes. E.g., the term “selective M₄ agonist”means a compound that has a measurably greater ability to act as an M₄agonist when compared to that compound's agonist activity with the othermuscarinic receptor subtype(s).

According to an alternative embodiment, the present invention provides amethod of treating a muscarinic receptor mediated disease in a mammal,such as a human, including the step of administering to said mammal acomposition comprising a compound of formulae I and II, or an embodimentthereof as set forth herein.

According to another embodiment, the present invention provides a methodof treating a disease mediated by a muscarinic receptor including thestep of administering to said mammal a composition comprising a compoundof formulae (I and II), or other embodiments thereof as set forth above.Preferably, said disease is mediated by M₁, or said disease is mediatedby M₄.

According to yet another embodiment, the present invention provides amethod of treating or reducing the severity of a disease in a patient,wherein said disease is selected from CNS derived pathologies includingcognitive disorders, Attention Deficit Hyperactivity Disorder (ADHD),obesity, Alzheimer's disease, various dementias such as vasculardementia, psychosis including schizophrenia, mania, bipolar disorders,pain conditions including acute and chronic syndromes, Huntington'sChorea, Friederich's ataxia, Gilles de la Tourette's Syndrome, DownsSyndrome, Pick disease, clinical depression, sudden infant deathsyndrome, Parkinson's disease, peripheral disorders such as reduction ofintra ocular pressure in Glaucoma and treatment of dry eyes and drymouth including Sjögren's Syndrome, wherein said method comprises thestep of contacting said patient with a compound according to the presentinvention.

According to an alternative embodiment, the present invention provides amethod of treating or reducing the severity of a disease in a patient,wherein said disease is selected from pain, psychosis (includingschizophrenia, hallucinations, and delusions), Alzheimer's disease,Parkinson's disease, glaucoma, bradhycardia, gastric acid secretion,asthma, or GI disturbances.

According to a preferred embodiment, the present invention is useful fortreating or reducing the severity of psychosis, Alzheimer's disease,pain, or Parkinson's disease.

All references cited within this document are incorporated herein byreference.

VII. Preparations and Examples

In order that the invention described herein may be more fullyunderstood, the following examples are set forth. It should beunderstood that these examples are for illustrative purposes only andare not to be construed as limiting this invention in any manner.

Preparation A: Synthesis ofN-(ethoxycarbonyl)-8-aza-bicyclo[3.2.1]octane-3-carbaldehyde

Sodium bis(trimethylsilyl)amide (6 mmol, 6 mL of 1 M solution in THF)was added to a suspension of 2.06 g (6.0 mmol) ofmethoxymethyltriphenylphosphonium chloride in 6 mL of THF at 0° C. underargon. After stirring at 0° C. for 15 min, the resulting dark redsolution was added via syringe to a solution of 0.79 g (4.0 mmol) ofN-(ethoxycarbonyl)tropinone (6) in 8 mL of THF at 0° C. and then stirredat room temerature for 4 h (an orange color persisted). The reactionmixture was quenched by adding sat. aq. NaCl (15 mL) and then extractedwith ether (25 mL×3). The combined organic extracts were dried overNa₂SO₄. The solid residue obtained after solvent evaporation was loadedonto a short silica gel column (3.5 cm×4 cm) to remove the phosphorousimpurities. The product was eluted with ether. After the solvent wasevaporated, the product enol ether was obtained as a brown oil which wasused in the next step without further purification.

The enol ether intermediate was dissolved in a solution of 12 mL of 2 NHCl and 20 mL of acetonitrile, and stirred at room temperature for 16 h.After removing the acetonitrile on a rotary evaporator, the aqueoussolution was extracted with ether (25 mL×3). The combined organicextracts were washed with sat. aq. NaHCO₃ (15 mL×2), sat. aq. NaCl (15mL) and then dried over Na₂SO₄. After the solution was evaporated todryness, the residue was purified by chromatography (SiO₂, 10%-20% EtOAcin Hexane as eluent).N-(ethoxycarbonyl)-8-aza-bicyclo[3.2.1]octane-3-carbaldehyde (0.65 g)was obtained as a colorless oil in an approximately 1:1 ratio of endoand exo isomers (77%). ESI-MS m/z 212.1 (MH⁺); ¹H NMR (300 MHz, CDCl₃) δ9.53 (s, 1H), 4.54 (br s, 1H), 4.38 (br s, 1H), 4.16 (m, 2H), 2.72 (m,2H), 2.38 (s, 1H), 2.32 (s, 1H), 2.10 (m, 3H), 1.69 (m, 2H), 1.29 (m,3H).

Preparation B: Synthesis of bicyclo[3.2.1]octane-2-carbaldehyde

Bicyclo[3.2.1]octane-2-carbaldehyde was prepared using an analogousprocedure as for Intermediate 1 from commercially availablebicyclo[3.2.1]octan-2-one. The crude products were used in the next stepwithout further purification.

Preparation C: Synthesis of7-oxa-bicyclo[2.2.1]hept-5-ene-2-carbaldehyde

To a stirred solution of furan (9) (15 mL, 200 mmol) and acrolein (13)(6.7 mL, 100 mmol) in DCM (25 mL) was slowly added AlCl₃ (666 mg, 5mmol) under argon at −43° C. (dry ice/isopropanol bath). The reactionmixture was stirred at −43° C. under argon for 30 min, and then quenchedwith sat. aq. K₂CO₃ (50 mL). After the reaction mixture was graduallywarmed to room temperature, it was extracted with ether (200 mL×5). Thecombined ether extracts were washed with sat. aq. K₂CO₃ (200 mL×2) andsat. aq. NaCl (200 mL×2), dried over MgSO₄, filtered, and concentratedto give 2.6 g of oily crude product7-oxa-bicyclo[2.2.1]hept-5-ene-2-carbaldehyde which was used in the nextstep without further purification. See references Laszlo, P.; Lucchetti,J. Tetrahedron Lett. 1984, 25, 4387-4388. Moore, J. A., Partain, E. M.III. J. Org. Chem. 1983, 48, 1105-1106. Dauben, W. G.; Krabbenhoft, H.O. J. Am. Chem. Soc. 1976, 98, 1992-1993. Nelson, W. L.; Allen, D. R.;Vincenzi, F. F. J. Med. Chem. 1971, 14, 698-702.

To a stirred solution of crude product7-oxa-bicyclo[2.2.1]hept-5-ene-2-carbaldehyde (2.6 g. 20 mmol) in 95%EtOH (200 mL) was added 10% Pd—C (0.25 g) at room temperature underargon. The mixture was shaken on a Parr hydrogenation apparatus for 4 hat room temperature under 30 psi of hydrogen. After the Pd catalyst wasremoved by filtration through a Celite pad, the Celite was washed withMeOH (15 mL×2), the combined extracts were concentrated under vacuum toyield 2.5 g of crude 7-oxa-bicyclo[2.2.1]hept-5-ene-2-carbaldehyde as apale yellow oil, which was used in the next step without furtherpurification.

Preparation D: Synthesis of ethyl 4-formylpiperidine-1-carboxylate

1.0 eq 4-piperidinemethanol (10.00 g, 86.8 mmol) was dissolved indichloromethane (350 mL), cooled in an ice-H₂O bath and treated dropwisewith a solution of 1.05 eq ethyl chloroformate (9.89 g, 91.1 mmol) indichloromethane (50 mL), followed by the dropwise addition of a solutionof 1.0 eq triethylamine (8.78 g) in dichloromethane (50 mL). Thereaction was stirred at ˜0° C. for 15 minutes, then at room temperaturefor 10 minutes. The reaction was diluted with dichloromethane (250 mL)and washed successively with (150 mL each) H₂O, 0.1 N HCl (aq) (×2),saturated brine, then dried (Na₂SO₄) and filtered. The filtrate wasconcentrated in vacuo to afford 15.60 g ethyl4-(hydroxymethyl)-piperidine-1-carboxylate as a viscous, palebluish-green oil. Yield=96%. ¹H-NMR (400 MHz, CDCl₃) δ 4.15 (br m, 2H),4.09 (q, J=7.1 Hz, 2H), 3.46 (d, J=6.4 Hz, 2H), 2.72 (br t, J=12.4 Hz,2H), 2.07 (s, 1H), 1.70 (m, 2H), 1.63 (m, 1H), 1.23 (t, J=7.2 Hz, 3H),1.12 (m, 2H); t_(R)=1.56 min [10-99% CH₃CN gradient over 5 mins with0.1% TFA (aq)]; Theoretical (M+H)⁺ m/z for C₉H₁₇NO₃=188.1; Found 188.0.

A solution of 1.2 eq oxalyl chloride (12.69 g, 0.10 mol) indichloromethane (150 mL) was cooled to approximately −78° C. and treateddropwise, under nitrogen, with a solution of 2.4 eq anhydrousdimethylsulfoxide (15.63 g, 0.20 mol) in dichloromethane (50 mL). 15minutes after the addition was complete, a solution of 1.0 eq ethyl4-(hydroxymethyl)-piperidine-1-carboxylate (15.60 g, 83.3 mmol) indichloromethane (50 mL) was added dropwise. 30 minutes after theaddition was complete, a solution of 3.0 eq triethylamine (25.30 g, 0.25mol) in dichloromethane (50 mL) was added dropwise and the reactionwarmed to room temperature. The reaction was stirred at room temperaturefor 1 hour, then quenched with saturated sodium bicarbonate (500 mL).The layers were separated and the aqueous layer extracted once withdichloromethane (200 mL). The pooled organic layers were washed with H₂O(3×100 mL), saturated sodium bicarbonate (1×100 mL) and saturated brine,then dried (Na₂SO₄) and filtered. The filtrate was concentrated in vacuoto afford 13.84 g ethyl 4-formylpiperidine-1-carboxylate as a viscousamber oil. Yield=90%. ¹H-NMR (400 MHz, CDCl₃) δ 9.64 (s, 1H), 4.10 (q,J=7.2 Hz, 2H), 4.00 (br m, 2H), 2.97 (m, 2H), 2.40 (m, 1H), 1.87 (br m,2H), 1.54 (m, 2H), 1.23 (t, J=7.0 Hz, 3H).

Preparation E: Synthesis of ethyl4-formyl-4-methylpiperidine-1-carboxylate

Diisopropylamine (3.14 mL; 22.23 mmol; 1.1 eq.) was dissolved in THF (60mL) and cooled to −78° C. Butyl lithium (2.5 M in hexane; 8.89 mL; 22.23mmol; 1.1 eq.) was then added and the solution was stirred for 30minutes at −78° C. Ethyl 1-benzylpiperidine-4-carboxylate (5 g; 20.21mmol; 1 eq.) was dissolved in THF (40 mL) and added to the LDA solutionat −78° C. The solution was stirred at −78° C. for 30 minutes andiodomethane (1.32 mL; 21.22 mmol; 1.05 eq.) was added. The solution wasslowly warmed to room temperature and stirred at room temperature for 1hour. Water (100 mL) was then added to the reaction followed by EtOAc(50 mL). The layers were separated and the aqueous layer was extractedwith EtOAc (2×50 mL). The combined organic layers were dried overNa₂SO₄, filtered, and concentrated under reduced pressure to afford theproduct (5.0 g, 94% yield) as an oil. The product was analytically pureand used without further purification. LC/MS m/z (M+1) 262.0, Retentiontime 1.78 minutes; (10-99% CH₃CN—H₂O gradient with 0.03% TFA, 5 min). ¹HNMR (400 MHz, CDCl₃) δ 7.24-7.14 (m, 5H), 4.08 (q, J=7.1 Hz, 2H), 3.40(s, 2H), 2.60-2.57 (m, 2H), 2.08-2.02 (m, 4H), 1.47-1.40 (m, 2H), 1.17(t, J=7.1 Hz, 3H), 1.10 (s, 3H).

1-Benzyl-4-methylpiperidine-4-carboxylate (5.0 g; 19.15 mmol) wasdissolved in Et₂O (50 mL) and cooled to 0° C. LiAlH₄ (1.0 g; 26.3 mmol)was slowly added portion-wise to the solution. After the addition wascomplete, the solution was slowly warmed to room temperature and stirredfor 1 h. The solution was then cooled to 0° C. and slowly quenched with1N NaOH (6 mL). The resultant white precipitates were filtered andwashed with EtOAc (100 mL). The combined organic layers wereconcentrated under reduced pressure to provide the product (3.9 g, 90%yield) as an oil which was used without further purification. LC/MS m/zM+1 220.0, retention time 0.64 minutes; (10-99% CH₃CN—H₂O gradient with0.03% TFA, 5 min). ¹H NMR (400 MHz, CDCl₃) δ 7.25-7.16 (m, 5H), 3.46 (s,2H), 3.30 (d, J=3.9 Hz, 2H), 2.51-2.46 (m, 2H), 2.26-2.20 (m, 2H),1.52-1.45 (m, 3H), 1.30-1.25 (m, 2H), 0.87 (s, 3H).

(1-benzyl-4-methylpiperidin-4-yl)methanol (3.9 g; 17.8 mmol) wasdissolved in MeOH (50 mL) and NH₄CO₂H (12.5 g; 178.0 mmol) was added.Pd/C (10% by weight, wet; 5.5 g) was then added and the system wasflushed with nitrogen and then with hydrogen. The reaction was stirredat room temperature overnight (18 h) and then filtered through a pad ofCelite. The solvent was removed under high vacuum to provide a solidthat was a mixture of the amino alcohol and NH₄CO₂H. The crude product(2.4 g as a mixture with NH₄COOH) was used in the next step withoutfurther purification. LC/MS m/z (M+1) 130.0, retention time 0.35 min;(10-99% CH₃CN—H₂O gradient with 0.03% TFA, 5 min). ¹H NMR (400 MHz,CDCl₃) δ 3.17 (s, 2H), 3.03-2.98 (m, 2H), 2.95-2.88 (m, 2H), 1.64-1.57(m, 2H), 1.36-1.31 (m, 2H), 0.89 (s, 3H).

(4-methylpiperidin-4-yl)methanol (2.4 g, a mixture of the amino alcoholand NH₄CO₂H) was suspended in DCM (70 mL). Et₃N (5 mL; 37.2 mmol) wasthen added followed by the drop-wise addition of ethyl chloroformate(1.05 mL, 13 mmol, 1.4 eq.). After 1 hour at room temperature, 1N HCl(70 mL) was added and the layers were separated. The aqueous layer wasextracted with DCM (70 mL) and the combined organic layers were driedover Na₂SO₄, filtered, and concentrated under high vacuum. The product(1.7 g, 47% yield over 2 steps) is obtained analytically pure as an oiland used without further purification. LC/MS m/z (M+1) 202.2, retentiontime 1.89 minutes; (10-99% CH₃CN—H₂O gradient with 0.03% TFA, 5 min). ¹HNMR (400 MHz, DMSO-d₆) δ 4.05 (q, J=7.1 Hz, 2H), 3.66 (dt, J=13.6, 4.7Hz, 2H), 3.32 (s, 2H), 3.11 (t, J=5.2 Hz, 1H), 3.11 (dd, J=23.9, 3.5 Hz,1H), 1.44-1.37 (m, 3H), 1.26-1.22 (m, 2H), 1.19 (t, J=7.1 Hz, 3H), 0.93(s, 3H).

To a 100 mL round bottom flask was added DCM (30 mL) and oxalyl chloride(0.88 mL; 10.13 mmol). The solution was cooled to −78° C. and treatedwith DMSO (1.19 mL; 16.88 mmol). The solution was stirred at −78° C. for20 minutes and then treated with ethyl4-(hydroxymethyl)-4-methylpiperidine-1-carboxylate (1.7 g; 8.44 mmol,dissolved in 10 mL of DCM). The solution was stirred for 30 minutes at−78° C. and then treated with Et₃N (3.53 mL; 25.32 mmol). The solutionwas stirred at −78° C. for 20 min and then slowly warmed to roomtemperature and stirred at room temperature for an additional 2 h. Thesolution was then treated with saturated aqueous NaHCO₃ (50 mL), dilutedwith DCM (50 mL), and the layers were separated. The organic layer waswashed with brine (50 mL), dried over Na₂SO₄, filtered, and concentratedunder reduced pressure to afford 1.6 g (95% yield) of the product as anoil which was used without further purification. LC/MS m/z (M+1) 200.0,retention time 2.23 minutes; (10-99% CH₃CN—H₂O gradient with 0.03% TFA,5 min). ¹H NMR (400 MHz, CDCl₃) δ 9.40 (s, 1H), 4.06 (q, J=7.1 Hz, 2H),3.66 (dt, J=13.6, 4.7 Hz, 2H), 3.09 (dd, J=10.1, 3.5 Hz, 1H), 3.06 (dd,J=10.2, 3.4 Hz, 1H), 1.86 (dt, J=13.6, 4.4 Hz, 2H), 1.42-1.30 (m, 2H),1.19 (t, J=7.1 Hz, 3H), 1.02 (s, 3H).

Preparation F: Synthesis of benzyl 4-oxotropane-N-carboxylate

Tropinone (10.0 g; 71.84 mmol) was dissolved in DCE (60 mL) and treateddrop-wise with 1-chloroethyl chloroformate ACE-Cl (14.5 mL; 19.11 g;133.7 mmol). The reaction was allowed to stir at room temperatureovernight and was then diluted with Et₂O (400 mL) and filtered. Thefiltrate was concentrated under reduced pressure to provide the crudechloroethyl carbamate. This compound was taken in MeOH (200 mL) andstirred at room temperature for 1 h, then concentrated under reducedpressure (at 55° C.) to provide the crude des-methyltropinone as the HClsalt (tan solid, 11.4 g, 98% yield). The crude material wasrecrystallized from acetonitrile to furnish the pure product as a whitecrystalline solid (5 g, 43% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 1.79(dd, J=15.0, 6.9 Hz, 2H), 2.09 (m, 2H), 2.40 (d, J=16.7 Hz, 2H), 3.02(dd, J=17.1, 4.3 Hz, 2H), 4.23 (s, 2H), 10.00 (br s, 2H)

Des-methyl tropinone (5.10 g; 31.55 mmol) was dissolved in CH₂Cl₂ (50mL) and treated with benzyl chloroformate (4.29 mL; 5.11 g; 29.98 mmol)DIPEA (16.48 mL; 12.23 g; 94.66 mmol) was added drop-wise (exothermicreaction). The resulting clear solution was allowed to stir at roomtemperature for 30 min and was subsequently diluted with 100 mL CH₂Cl₂.The organic phase was washed with 1 N HCl (2×100 mL), dried on Na₂SO₄and concentrated to provide the crude product (7.2 g, 88% yield). ¹H NMR(400 MHz, CDCl₃) δ 1.71 (dd, J=15.0, 7.2 Hz, 2H), 2.12 (m, 2H), 2.38 (d,J=15.9 Hz, 2H), 2.67 (m, 2H), 4.62 (s, 2H), 5.22 (s, 2H), 7.38 (m, 5H).

EXAMPLE 1

To a solution of compound N-Boc Spiroindane 1a (60.0 g, 0.21 mol) inCH₂Cl₂ (1000 mL) was added H₂O (500 mL), TBAB (6.9 g, 0.02 mol) and KOH(3.5 g, 0.06 mol) and followed by addition of KMnO₄ (70.0 g, 0.45 mol)in several portions. After stirring for two days at 35° C., anotherquantity of KMnO₄ (70.0 g, 0.45 mol) was added and the mixture wascontinued to stir for 2 days. After Na₂SO₃ (103.0 g, 1.0 mol) was addedin portions at 5° C., the mixture was extracted with EtOAc. The combinedorganic layers were dried over anhydrous Na₂SO₄ and evaporated undervacuum. The residue was purified by column chromatography (PE/EtOAc:5/1) to yield 1b (30.0 g, 47.7%). ¹H NMR (CDCl₃) δ: 7.74-7.72 (m, 1 H),7.66-7.64 (m, 1 H), 7.62-7.61 (m, 1 H), 7.49-7.38 (m, 1H), 4.22-4.20 (m,2 H), 2.89-2.82 (m, 2 H), 2.63 (s, 2 H), 2.02-1.94 (m, 2 H), 1.56-1.52(m, 2 H), 1.49 (s, 9H). MS (ESI) m/z (M+H⁺) 246.0/202.1.

Boc-protected starting material 1b (400.0 mg; 1.33 mmol) was dissolvedin CH₂Cl₂ (1.5 mL) and treated with TFA (1.5 mL). The reaction wasallowed to stir at room temperature for 1 h and was then quenched byadding H₂O (5 mL) and Et₂O (7 mL). The layers were separated, and theaqueous layer was brought to a basic pH by addition of solid KOH. Theresulting emulsion was extracted with Et₂O (3×10 mL). The combinedorganic extracts were dried on Na₂SO₄ and concentrated to yield thedesired product 1c as a colorless oil that solidifies upon standing (220mg, 82% yield). LC/MS m/z 202.2 [M+H]⁺, retention time 0.72 min (10-99%CH₃CN—H₂O gradient with 0.03% TFA, 5 min).

Intermediate 1c (40 mg; 0.2 mmol) was suspended in DCE (1 mL) andtreated with (1R,2R,4R)-bicyclo[2.2.1]hept-5-ene-2-carbaldehyde (31 mg;0.26 mmol; 1.300 eq.) in DCE (0.5 mL), followed by portion-wise additionof NaBH(OAc)₃ (127 mg; 0.6 mmol) The reaction was allowed to stir atroom temperature for 1 h and was then quenched with MeOH (1 mL) andallowed to stir for another 30 min. The crude reaction mixture waspurified by HPLC (10-99% CH₃CN gradient with 0.03% TFA, 15 min) toprovide the purified compound no. 237. LC/MS m/z 308.2 [M+H]⁺, retentiontime 2.08 (10-99% CH₃CN—H₂O gradient with 0.03% TFA, 5 min).

¹H NMR (400 MHz, DMSO-d₆) δ 9.47 (br s, 1H), 7.81-7.77 (m, 1H), 7.66 (d,J=J=7.4 Hz, 1H), 7.59 (d, J=7.8 Hz, 7.53-7.49 (m, 1H),J6.27 (dd, J=5.7,3.0 Hz, 1H), 6.05 (dd, J=5.7, 2.8 Hz, 1H), 3.60 (t, J=12.7 Hz, 3H),3.11-2.90 (m, 4H), 2.85-2.74 (m, 4H), 2.29 (t, J=13.0 Hz, 2H), 2.05-1.99(m, 1H), 1.76 (d, J=14.2 Hz, 2H), 1.39-1.35 (m, 1H), 1.29 (d, J=8.2 Hz,1H), 0.71-0.66 (m, 1H).

EXAMPLE 2

1.0 eq of the Boc-protected spiroindanone 2a (2.06 g, 6.84 mmol) wasdissolved in anhydrous tetrahydrofuran (5 mL) and added drop-wise, undernitrogen, to an ice-cold (˜0° C.) suspension of 2.2 eq sodium hydride(600 mg, 60% dispersion in mineral oil, 15.0 mmol) in anhydroustetrahydrofuran (10 mL). A solution of 10.0 eq iodomethane (9.71 g, 68.4mmol) in anhydrous tetrahydrofuran (5 mL) was then added drop-wise over20 min. The reaction was warmed to room temperature and stirred for 2hours under nitrogen. The reaction mixture was concentrated underreduced pressure and slowly treated with H₂O (25 mL). The product wasextracted with ethyl acetate (2×50 mL) and the pooled extracts washedwith saturated sodium bicarbonate and saturated brine, then dried(Na₂SO₄) and filtered. The filtrate was concentrated in vacuo to afford2.41 g crude product 2b as a viscous, pale yellow oil. Yield=˜100%.¹H-NMR (400 MHz, acetone-d₆) δ 7.90 (d, J=6.8 Hz, 1H), 7.71 (m, 2H),7.49 (t, J=7.4 Hz, 1H), 3.75 (m, 2H), 3.56 (br m, 2H), 1.89 (m, 2H),1.64 (br m, 2H), 1.48 (s, 9H), 1.12 (s, 6H); t_(R)=3.50 min [10-99%CH₃CN gradient over 5 min with 0.1% TFA (aq)]; Theoretical (M+H)⁺ m/zfor C₂₀H₂₇NO₃=330.2; Found 330.2.

The gem-dimethyl spiroindanone 2b (379 mg, 1.15 mmol) was dissolved indichloromethane (2.5 mL), cooled in an ice-H₂O bath and treated slowlywith trifluoroacetic acid (2.5 mL). The reaction was stirred for 30 minat ˜0° C., then concentrated under reduced pressure. The oil obtainedwas dissolved in acetonitrile and re-concentrated under reducedpressure. The crude TFA salt was treated with 1.0 N NaOH (5 mL) andextracted with ethyl acetate (2×30 mL). The pooled extracts were washedwith H₂O and saturated brine, then dried (Na₂SO₄) and filtered. Thefiltrate was concentrated in vacuo to afford 210 mg of the crude freebase 2c as a colorless semi-solid. Yield=80%. t_(R)=1.52 min [10-99%CH₃CN gradient over 5 min with 0.1% TFA (aq)]; Theoretical (M+H)+m/z forC₁₅H₁₉NO=230.2; Found 230.2

The crude free base 2c (53 mg, 0.23 mmol) was dissolved in anhydrous1,2-dichloroethane (1.0 mL) and treated with N-(carbethoxy)-4-tropinone(55 mg, 0.28 mmol), followed by titanium tetraisopropoxide (202 μL, 196mg, 0.69 mmol). The vial was flushed with nitrogen and stirred at roomtemperature for 2.5 days. The reaction was diluted with methanol (1.0mL), cooled in an ice-H₂O bath and treated with sodium borohydride (17mg, 0.46 mmol). The reaction was warmed to room temperature and stirredthereafter for 30 min. The reaction was then quenched with 1.0 N NaOH(750 μL), diluted with methanol (1.5 μL) and stirred at room temperaturefor 10 min. The suspension obtained was centrifuged (3K rpm, 10 min) andthe supernatant concentrated under reduced pressure. The residueobtained was dissolved in DMSO:methanol (1.5 mL, 1:1 v/v), filtered, andpurified by reverse-phase HPLC (2-40% CH₃CN gradient over 10 min with0.1% TFA (aq), 35 mL/min, 1.0 mL injected) to produce the compound no.277 as a TFA salt. t_(R)=2.12 min [10-99% CH₃CN gradient over 5 min with0.1% TFA (aq)]; Theoretical (M+H)⁺ m/z for C₂₅H₃₄N₂O₃=411.3; Found411.2.

EXAMPLE 3

The starting Spiroindane 3a (45 mg, 0.2 mmol) was suspended in DCE (1mL) and treated with (1S,2S,4S)-bicyclo[2.2.1]hept-5-ene-2-carbaldehyde(25 mg, 0.2 mmol) in DCE, followed by the addition of NaBH(OAc)₃ (63 mg,0.3 mmol). The reaction was allowed to stir at room temperature for 1 hand was then quenched with MeOH (0.5 mL) and allowed to stir for another30 min (until gas evolution stopped). The crude reaction mixture wasfiltered, then purified by HPLC (10-99% CH₃CN/0.05% TFA gradient) toyield compound no. 312. LC/MS m/z 294.4 [M+H]⁺, retention time 2.33 min(RP—C₁₈, 10-99% CH₃CN/0.05% TFA); ¹H NMR (400 MHz, DMSO-d₆) δ 9.33 (brs, 1H), 7.25-7.17 (m, 3H), 7.13 (d, J=6.9 Hz, 1H), 6.27-6.26 (m, 1H),6.06-6.04 (m, 1H), 3.56-3.40 (m, 3H), 3.11-3.03 (m, 2H), 2.98-2.78 (m,6H), 2.09-1.98 (m, 5H), 1.67 (d, J=13.9 Hz, 2H), 1.36 (t, J=8.0 Hz, 1H),1.29 (d, J=8.2 Hz, 1H), 0.70-0.66 (m, 1H).

EXAMPLE 4

To a solution of 2-amino-4-chloro-phenol 4a (50 g, 0.35 mol) in HCl (2.5mol, 500 mL) was added drop-wise a solution of sodium nitrite (25.25 g,0.35 mol) in water (50 mL) at 0° C. The mixture was stirred at thistemperature for 30 min. Then a cooled solution of KI (70 g, 0.42 mol) inH₂O (100 mL) was slowly added at 0° C. After addition, the mixture wasallowed to warm to room temperature and stirred overnight. The reactionmixture was diluted with ethyl acetate (200 mL) and the separatedaqueous phase was extracted with ethyl acetate (100 mL×3). The combinedorganic fraction was washed with Na₂S₂O₃ (10%, 100 mL), water (100 mL×2)and brine (200 mL), dried over Na₂SO₄ and concentrated to dryness. Theresidue was purified by column on silica gel to afford4-chloro-2-iodo-phenol 4b as a yellow solid (46 g, yield 51.7%). ¹H NMR(400 MHz, CDCl₃): δ 7.67 (d, J=2.4 Hz, 1 H), 7.21 (dd, J=2.4, 8.4, Hz, 1H), 6.91 (d, J=8.4 Hz, 1 H), 5.33 (s, 1 H).

To a solution of 4-chloro-2-iodo-phenol 4b (20.32 g, 0.08 mol),(1-benzyl-1, 2, 3, 6-tetrahydro-pyridin-4-yl)-methanol (20.5 g, 0.08mol) and triphenylphosphine (23.58 g, 0.09 mol) in dry THF (150 mL) wasadded DEAD (17.4 g, 0.09 mol) at 0° C. under nitrogen atmosphere. Afteraddition, the mixture was stirred at room temperature overnight. Themixture was concentrated to dryness and the residue was basified byNa₂CO₃ solution (10% 100 mL) and extracted with ethyl acetate (100mL×3). The combined organic layers were washed with water (100 mL×2) andbrine (200 mL), dried over Na₂SO₄, concentrated to dryness. The residuewas purified by column on silica gel to afford1-benzyl-4-(4-chloro-2-iodo-phenoxymethyl)-1,2,3,6-tetrahydro-pyridine4c (30 g, 86%). ¹H NMR (400 MHz, CDCl₃): δ 7.73 (d, J=2.4 Hz, 1 H),7.22-7.38 (m, 6 H), 6.70 (d, J=8.8 Hz, 1 H), 5.82 (s, 1 H), 4.43 (s,2H), 3.63 (s, 2 H), 3.05 (s, 2 H), 2.67 (t, J=5.6 Hz, 2 H), 2.28 (s, 2H).

To a refluxing solution of1-benzyl-4-(4-chloro-2-iodo-phenoxymethyl)-1,2,3,6-tetrahydro-pyridine4c (26.7 g, 0.06 mol) and AIBN (0.05 g, 0.003 mol) in dry benzene wasadded a solution of Bu₃SnH (40 g, 0.137 mol) in benzene (100 mL) over 1h under nitrogen atmosphere. After addition, the mixture was refluxedfor 3 hr and additional AIBN (0.5 g, 0.003 mol) and Bu₃SnH (20 g, 0.68mol) were added. After refluxing for 4 hr, the mixture was concentratedto dryness, and EtOAc (100 mL) and HCl (10%, 40 mL) were added. Theprecipitate was filtered and washed with petroleum ether to give2,3-dihydro-1′-benzyl-5-chlorospiro (benzofuran-3,4′-piperidine) as itsHCl salt, which was basified by NaHCO₃ solution to give2,3-dihydro-1′-benzyl-5-chlorospiro (benzofuran-3,4′-piperidine) 4d (13g, 68%).

To a solution of 2,3-dihydro-1′-benzyl-5-chlorospiro(benzofuran-3,4′-piperidine) 4d (13 g, 0.04 mol) in CH₂Cl₂ (130 mL) wasadded drop-wise 1-chloroethyl chloroformate (7.2 g, 0.05 mol). Themixture was stirred for 3 hr at room temperature and then concentratedto dryness. The residue was dissolved in CH₃OH (30 mL) and the solutionwas heated to reflux for 30 min. After removing of the solvent, etherwas added. The resulted solid was filtered and washed with ether to thedebenzylated product 4e as the HCl salt (5.5 g, yield 48%). ¹H NMR (400MHz, DMSO-d₆): δ 9.08 (br s, 1 H), 7.16-7.19 (m, 2 H), 6.82 (d, J=8.4Hz, 1 H), 4.50 (s, 2 H), 3.25-9.29 (m, 2 H), 2.98-2.92 (m, 2 H),2.12-2.05 (m, 2 H), 1.83-1.8 (m, 2 H).

The chloro-dihydrobenzofuran spiro amine 4e (3.18 mmol) was dissolved inanhydrous DCE (15 mL) and treated with triethylamine (322 mg, 3.18mmol), followed by (+)-2-norcamphor (421 mg, 3.82 mmol), acetic acid(382 mg, 6.36 mmol) and NaBH(OAc)₃ (1.35 g, 6.37 mmol). The reaction wasstirred vigorously under nitrogen at room temperature for ˜36 hours. Thereaction was quenched with methanol (15 mL) and stirred vigorously for10 min at room temperature. The reaction mixture was then concentratedunder reduced pressure and the residue obtained dissolved in a mixtureof DMSO:CH₃OH (20 mL, 1:3 v/v). The solution was filtered and purifiedby reverse-phase HPLC (2-99% CH₃CN/0.05% TFA, 35 mL/min). The combinedpure fractions were concentrated under reduced pressure until ˜25 mL ofsolvent remained. The suspension was treated with 1 N NaOH (25 mL) andextracted with CH₂Cl₂ (3×50 mL). The combined organic extracts werewashed with H₂O, saturated brine, dried over Na₂SO₄ and filtered. Thefiltrate was concentrated under reduced pressure to afford 522 mg purefree base (1.64 mmol) as a crystalline white solid. The free base wasreadily dissolved in anhydrous diethyl ether (10 mL) and treated with1.0 eq 1 N ethereal HCl (1.7 mL). The thick, gelatinous suspensionobtained was cooled in an ice/H₂O bath for 1 hour, filtered, rinsed withEt₂O (3×10 mL), and dried overnight under reduced pressure to yieldcompound no. 1 as a fine white powder. ¹H-NMR (400 MHz, DMSO-d₆) δ 10.1(br s, 1 H), 7.77 (d, J=2.2 Hz, 0.2 H), 7.21 (dd, J=2.3 Hz, 8.5 Hz, 1H),7.08 (d, J=2.3 Hz, 0.8 H), 6.85 (d, J=8.5 Hz, 0.8 H), 6.84 (d, J=8.5 Hz,0.2H), 4.52 (s, 1.6 H), 4.45 (s, 0.4 H), 3.41 (m, 1.8 H), 3.24 (m, 0.8H), 3.01 (br m, 1.6 H), 2.63 (br m, 2H), 2.44 (m, 0.9 H), 2.27 (br s,1.1H), 1.86 (br m, 4H), 1.51 (br m, 3.3H), 1.39 (br m, 2.7H), 1.24 (brm, 0.7H); LC/MS m/z 318.0 [M+H]⁺, retention time 2.14 min (RP—C₁₈,10-99% CH₃CN/0.05% TFA).

EXAMPLE 5

The starting material 5a (54 mg, 0.2 mmol, 1.0 eq) was suspended in DCE(1 mL) and treated with(1R,2R,4R)-bicyclo[2.2.1]hept-5-ene-2-carbaldehyde (31 mg, 0.26 mmol,1.3 eq) in DCE (0.5 mL), followed by portion-wise addition of NaBH(OAc)₃(127 mg, 0.6 mmol). The reaction was allowed to stir at room temperaturefor 3 h and was then quenched with MeOH (2 mL) and allowed to stir foranother hour (until gas evolution stopped). The reaction mixture wasthen diluted with H₂O (5 mL) and extracted with Et₂O (10 mL). Theorganic layer was treated with 1 N HCl (5 mL) and formation of aninsoluble precipitate was observed. The biphasic emulsion was filtered,and the white precipitate was washed with Et₂O (3×5 mL) and hexanes(2×10 mL) and dried under vacuum to provide the pure HCl salt ofcompound no. 64 as white shiny platelets. LC/MS m/z 344.0 [M+H]⁺,retention time 2.56 min (RP—C₁₈, 10-99% CH₃CN/0.05% TFA). ¹H NMR (400MHz, DMSO-d₆)δ 10.11 (s, 1H), 7.37 (d, J=2.4 Hz, 1H), 7.10 (d, J=2.5 Hz,1H), 6.74 (d, J=8.7 Hz, 1H), 6.18 (q, J=2.8 Hz, 1H), 6.02 (q, J=2.7 Hz,1H), 4.05-4.03 (m, 2H), 3.37-3.32 (m, 2H), 3.08-2.97 (m, 3H), 2.85-2.77(m, 2H), 2.72-2.65 (m, 1H), 2.49-2.45 (m, 3H), 1.98-1.90 (m, 3H),1.72-1.70 (m, 2H), 1.26 (dd, J=33.4, 7.3 Hz, 2H), 0.63 (d, J=10.5 Hz,1H).

EXAMPLE 6

The fluoroindoline 6a (1.22 g; 4.0 mmol) was suspended in DCE (10 mL)and cooled to −30° C. A solution of(1R,2R,4R)-bicyclo[2.2.1]hept-5-ene-2-carbaldehyde (635 mg; 5.2 mmol) indry DCE (2 mL) was added, followed by portion-wise addition ofNaBH(OAc)₃ (1.18 g; 5.6 mmol). The reaction was stirred at −30° C. undernitrogen for 90 min then at room temperature until complete consumptionof starting material was observed by LC/MS (30 h). The reaction wasquenched with MeOH (10 mL) and allowed to stir vigorously for 30 min(until gas evolution stopped). The reaction was diluted with 1N HCl (80mL) and Et₂O (50 mL). Formation of a white precipitate can be observedas the HCl salt of the desired product is insoluble in both phases. Thebiphasic mixture was filtered, and the precipitate was washed with Et₂O(2×20 mL) and hexanes (2×30 mL) and dried under high vacuum to providethe product 6b as the corresponding HCl salt (white powder, 1.41 g,78.5% yield).

The HCl salt 6b (1.4 g; 3.1 mmol) was dissolved in CH₂Cl₂ (10 mL) andTFA (10 mL) was added. The reaction mixture was allowed to stir at roomtemperature for 1 h. The reaction was quenched with water (100 mL) anddiluted with hexanes (40 mL) and Et₂O (50 mL). The layers wereseparated, and the organic layer was extracted with H₂O (2×100 mL). Thecombined aqueous layers were washed with Et₂O (50 mL) then neutralizedwith solid KOH (under dry-ice bath cooling) until formation of an oilysuspension was observed. The suspension was extracted with EtOAc (3×100mL) and CH₂Cl₂ (100 mL), and the combined organic extracts were driedover Na₂SO₄ and concentrated to provide the crude product as a lightbrown oil. The amine was dissolved in 15 mL Et₂O and treated with 2 NHCl in ether (1.5 mL, 3.0 mmol, 0.96 eq). After 20 min of stirring theresulting precipitate was vacuum filtered under a nitrogen atmosphere,washed with 50 mL Et₂O, 30 mL Et₂O:CH₃CN (5:1) and 40 mL hexanes anddried under high vacuum to provide the HCl salt of compound no. 147 asan off-white powder. LC/MS m/z 313.30 [M+H]⁺, retention time 1.73 min(RP—Cl₈, 10-99% CH₃CN/0.05% TFA). ¹H NMR (400 MHz, MeOD) δ 0.83 (ddd,J=5.8, 2.6 Hz, 1H), 1.41 (d, J=8.4 Hz, 1H), 1.54 (m, 1H), 2.01 (s, 1H),2.05 (d, J=3.9 Hz, 1H), 2.15 (ddd, J=6.1, 3.1 Hz, 1H), 2.23 (m, 2H),2.60 (m, 1H), 2.86 (dd, J=13.0, 7.4 Hz, 1H), 2.93 (s, 1H), 3.11 (m, 4H),3.66 (m, 4H), 6.09 (d, J=2.8 Hz, 1H), 6.33 (d, J=3.0 Hz, 1H), 6.90 (m,3H).

EXAMPLE 7

Starting material 7a hydrochloride (2.17 g, 6.40 mmol) was suspended inanhydrous DCE (30 mL) and treated with triethylamine (648 mg, 6.40mmol), followed by (−)-2-norcamphor (706 mg, 6.40 mmol), acetic acid(770 mg, 12.8 mmol) and NaBH(OAc)₃ (2.72 g, 12.8 mmol). The reaction wasstirred vigorously under nitrogen at room temperature for 72 h (˜77%conversion by LC/MS at 220 nm). The reaction was quenched with methanol(10 mL) and stirred vigorously for 10 min at room temperature. Thereaction mixture was then concentrated under reduced pressure and theresidue obtained dissolved in a 1:1 mixture of DMSO:CH₃OH (30 mL). Themixture was centrifuged (3,000 rpm, 10 min) and the supernatant filteredand purified by reverse-phase HPLC (10-99% CH₃CN/0.05% TFA, 50 mL/min).The combined pure fractions were concentrated under reduced pressure toafford 2.25 g of the N-Boc intermediate 7b (isolated as the TFA salt) asan off-white solid (69% isolated yield, Purity=99+%). LC/MS (RP—C₁₈,10-99% CH₃CN/0.05% TFA gradient over 5 min) m/z 397.4 [M+H]⁺, retentiontime 2.70 min.

The N-Boc intermediate 7b (2.25 g, 4.41 mmol) was dissolved indichloromethane (25 mL) and slowly treated with trifluoroacetic acid (15mL). The reaction was stirred at room temperature for 30 min, and thenconcentrated under reduced pressure. The oil obtained was slowly treatedwith 1 N NaOH (100 mL) and extracted with CH₂Cl₂ (2×75 mL). The combinedextracts were washed with H₂O, saturated brine, dried over Na₂SO₄ andfiltered. The filtrate was concentrated under reduced pressure to afford1.147 g (3.87 mmol) free base as a yellow oil. The free base wasdissolved in a minimal volume of anhydrous diethyl ether and treatedwith 0.95 eq 1 N ethereal HCl. The suspension was cooled in an ice/H₂Obath for 1 h, filtered, rinsed with Et₂O, and dried overnight underreduced pressure to yield 1.213 g (57% yield) of the desired product 7cas a fine, off-white to very pale yellow powder. LC/MS (RP—C₁₈, 10-99%CH₃CN/0.05% TFA gradient over 5 min) m/z 297.2 [M+H]⁺, retention time1.72 min.

The deprotected amine HCl salt 7c (33 mg, 0.10 mmol) was suspended inanhydrous CH₃CN (1.0 mL) and treated with triethylamine (20 mg, 0.20mmol), followed by methanesulfonyl chloride (14 mg, 0.12 mmol). Thereaction was stirred at room temperature for 10 min, then quenched withDMSO:CH₃OH (1.0 mL, 1:1 v/v) and centrifuged (4000 rpm, 7 min). Thesupernatant was filtered and purified by reverse-phase HPLC (2-99%CH₃CN, 50 mL/min, 2.0 mL injected) to yield the desired compound no. 231as the TFA salt. LC/MS (RP—C₁₈, 10-99% CH₃CN/0.05% TFA gradient over 5min) m/z 375.0 [M+H]⁺, retention time 2.08 min.

EXAMPLE 8

Boc-protected fluoroindoline 8a (1.41 g; 4.11 mmol) and benzyl4-oxotropane-N-carboxylate (1.07 g; 4.11 mmol) were dissolved in amixture of DCE (5 mL) and DME (5 mL) and placed under a nitrogenatmosphere. TEA (0.57 mL; 0.42 g; 4.11 mmol) was added, followed byTi(OiPr)₄ (1.21 mL; 1.17 g; 4.11 mmol) and the reaction was allowed tostir at room temperature for 60 h. The reaction mixture was diluted with30 mL MeOH and cooled to −40° C. to −50° C. NaBH₄ (0.6 g; 13.45 mmol)was added portion-wise over 30 min and the reaction was allowed to stirat −40° C. to −20° C. until bubbling subsided (3 h), then warmed slowlyto room temperature and was stirred for 2 h. The sticky suspension wasfiltered through a pad of Celite, and the filter cake was washed withMeOH (2×30 mL) and Et₂O (3×50 mL). The filtrate was separated into thecorresponding layers, and the aqueous layer was extracted with Et₂O(2×50 mL). The combined organic extracts were dried over Na₂SO₄ andconcentrated to provide the crude product as a white foam. This materialwas dissolved in Et₂O (400 mL) and treated with 1 N aq. HCl (500 mL) andthe mixture was vigorously stirred for 20 min. The resulting biphasicsuspension was filtered, the precipitate was washed with HCl 1N (2×30mL), H₂O (2×30 mL) and Et₂O (3×30 mL) and dried. To remove the unreactedstarting material by conversion to the corresponding ethyl carbamate,the crude HCl salt was suspended in acetonitrile (10 mL) and treatedsequentially with ethyl chloroformate (1 mL) and triethylamine (2 mL).After 10 min, the mixture was diluted with Et₂O (300 mL) and poured onto1 N aq HCl (300 mL). The biphasic suspension was filtered, and theprecipitate was washed with HCl 1N (2×30 mL), H₂O (2×30 mL) and Et₂O(3×30 mL) and dried to provide the desired product 8b hydrochloridesalt. LC/MS m/z [M+H]+550.4 retention time 2.93 min (10-99% CH₃CN—H₂Ogradient with 0.03% TFA, 5 min).

Cbz-protected starting material 8b (1.140 g; 1.945 mmol) was dissolvedin methanol (20 mL) and treated with 10% wet Pd/C (1.14 g) and NH₄COOH(2.45 g; 38.9 mmol) The mixture was allowed to stir vigorously overnightunder an empty balloon (for venting). LC/MS analysis shows completeconversion to the desired product. The reaction mixture was filteredthrough a pad of Celite under a nitrogen atmosphere, and the filter cakewas rinsed with methanol (4×30 mL). The filtrate was concentrated toprovide the crude product, which was taken up in a mixture of EtOAc (100mL) and NaHCO₃ sat. (100 mL). The layers were separated, the aqueouslayer was extracted with EtOAc (2×100 mL), Et₂O (100 mL), and CH₂Cl₂(2×100 mL). The combined organic layers were dried over Na₂SO₄ andconcentrated to provide the crude product 8c as a white foam (707 mg,87% yield). LC/MS m/z 416.4 [M+H]⁺, retention time 2.26 (10-99%CH₃CN—H₂O gradient with 0.03% TFA, 5 min)

Compound 8c (250.0 mg; 0.60 mmol) was dissolved in DCM (15 mL) andtreated sequentially with methoxyethyl chloroformate (138.4 uL; 166.1mg; 1.203 mmol) and TEA (401.7 uL; 291.7 mg; 2.89 mmol). After 10 min,the reaction mixture was diluted with DCM (30 mL) and washed withsaturated NaHCO₃ solution (30 mL). The aqueous layer was extracted withDCM (30 mL) and the combined organic extracts were dried on Na₂SO₄ andconcentrated to provide the desired product 8d which was taken to thenext step without further purification. LC/MS m/z 518.0 [M+H]⁺,retention time 2.43 min (10-99% CH₃CN—H₂O gradient with 0.03% TFA, 5min).

Intermediate 8d was dissolved in a mixture of DCM (15 mL) and TFA (20mL) and allowed to stir at room temperature for 2 h. The reactionmixture was concentrated, dissolved in water (20 mL) and the pH wasadjusted to basic by portion-wise addition of solid KOH. The resultingsuspension was extracted with DCM (3×30 mL) and Et₂O (30 mL) and theorganic extracts were dried over Na₂SO₄, and then concentrated toprovide the free base of the desired product. The material was dissolvedin Et₂O (20 mL) and treated with excess 1N HCl in ether (2 mL). Theresulting suspension was filtered under nitrogen and the filtrate waswashed with Et₂O (3×10 mL) and dried under vacuum to provide the desiredproduct 8e as an off white solid (232 mg, 85% yield over 2 steps). LC/MSm/z 418.2 [M+H]⁺, retention time 1.16 min (10-99% CH₃CN—H₂O gradientwith 0.03% TFA, 5 min).

Intermediate 8e (230.0 mg; 0.51 mmol) was suspended in DCM (15 mL) andtreated sequentially with dimethyl carbamoyl chloride (931.3 uL; 1089.7mg; 10.13 mmol) and TEA (704.8 uL; 511.70 mg; 5.07 mmol). The reactionwas allowed to stir overnight at room temperature, and then the mixturewas diluted with DCM (30 mL) and washed with saturated NaHCO₃ solution(30 mL). The aqueous layer was extracted with DCM (30 mL) and thecombined organic extracts were dried over Na₂SO₄ and concentrated toprovide the free base of the desired product. This material wasdissolved in Et₂O (20 mL) and treated with excess 1N HCl in ether (3mL). The resulting suspension was filtered under nitrogen and thefiltrate was washed with Et₂O (3×10 mL) and dried under vacuum toprovide the desired compound no. 119 as an off-white solid. LC/MS m/z489.4 [M+H]⁺, retention time 2.20 min (10-99% CH₃CN—H₂O gradient with0.03% TFA, 5 min). ¹H NMR (400 MHz, DMSO-d₆) δ 1.66 (d, J=7.0 Hz, 2H),1.82 (s, 4H), 1.86 (s, 2H), 1.92 (s, 2H), 2.07 (s, 2H), 2.22 (t, J=12.1Hz, 2H), 2.87 (s, 6H), 3.05 (q, J=11.1 Hz, 2H), 3.28 (s, 3H), 3.53 (m,4H), 3.73 (m, 1H), 4.15 (d, J=4.4 Hz, 2H), 4.27 (s, 2H), 6.90 (dd,J=8.3, 2.4 Hz, 1H), 7.00 (m, 2H), 10.41 (s, 1H).

EXAMPLE 9

Example 9: Bromo-spiroindoline 9a (1.5 g, 4.08 mmol) was dissolved inanhydrous dichloromethane (20 mL) and cooled to 0° C. To the rapidlystirring solution was added acetyl chloride (0.481 g, 6.13 mmol)followed by triethylamine (0.853 mL, 6.13 mmol). The reaction mixturewas stirred at room temperature for 1 h. Then mixture was concentratedunder reduced pressure to afford desired product 9b as viscous paleyellow oil and carried to the next step without further purification.LC/MS (RP—C₁₈, 10-99% CH₃CN/0.05% TFA gradient over 5 min) m/z 411.0[M+H]⁺, retention time 3.39 min.

The intermediate 9b was dissolved in 10 mL of dichloromethane andtreated with trifluoroacetic acid (10 mL). The reaction was stirred atroom temperature for 30 min, and then concentrated under reducedpressure. The oil obtained was re-dissolved in acetonitrile,re-concentrated under reduced pressure, treated with 2 N NaOH (25 mL)and extracted with dichloromethane (2×50 mL). The combined extracts werewashed with saturated NaHCO₃, saturated brine, dried over Na₂SO₄ andfiltered. The filtrate was concentrated under reduced pressure to affordcrude free base 9c as a pale yellow oil. LC/MS (RP—C₁₈, 10-99%CH₃CN/0.05% TFA gradient over 5 min) m/z 309.7 [M+H]⁺, retention time2.07 min.

Intermediate 9c (1.260 g, 4.08 mmol) was dissolved in anhydrous1,2-dichloroethane (10 mL) and treated with 2 eq of1-carbethoxy-4-piperidone (1.393 g, 8.16 mmol), followed by glacialacetic acid (0.490 g, 8.16 mmol) and sodium triacetoxyborohydride (1.721g, 8.16 mmol). The reaction was stirred at room temperature undernitrogen for 48 h. The reaction was diluted with dichloromethane (50mL), quenched with 1.0 N NaOH (20 mL) and stirred vigorously at roomtemperature for 30 min. The layers were separated and the aqueous layerextracted with DCM (2×20 mL). The pooled organic layers were washed withH₂O (20 mL), brine (20 mL), then dried over Na₂SO₄ and filtered. Thefiltrate was concentrated under reduced pressure to afford 1.8 g crudeproduct 9d as pale yellow oil (˜95% yield). An analytical sample wassubjected to reverse-phase HPLC purification (2-50% CH₃CN gradient over13 min with 0.1% TFA (aq), 35 mL/min, 1.0 mL injected). The remainder ofthe material was taken to the next step without purification. ¹H NMR(400 MHz, DMSO-d₆) δ 9.94 (s, 1H), 8.00 (d, J=8.6 Hz, 1H), 7.41 (d,J=8.6 Hz, 1H), 7.27 (d, J=2.0 Hz, 1H), 4.13 (m, 4H), 4.06 (q, J=7.1 Hz,2H), 3.54-3.46 (m, 3H), 3.16 (q, J=11.0 Hz, 2H), 2.83 (bs, 2H), 2.21 (s,3H), 2.17-2.07 (m, 4H), 1.93 (d, J=15.6 Hz, 2H), 1.66-1.55 (m, 2H), 1.20(t, J=7.0 Hz, 3H). LC/MS (RP—C₁₈, 10-99% CH₃CN/0.05% TFA gradient over 5min) m/z 467.2 [M+H]⁺, retention time 1.97 min.

Product 9d (46.4 mg, 0.1 mmol) was mixed with 4-methylphenyl boronicacid (14 mg, 0.1 mmol) in 1 mL of CH₃CN and 1 mL of 2 M aq. Na₂CO₃. Themicrowave tube was purged with N₂ and 7 mg (10 mol %) of PdCl₂(dppf) wasadded and tube was again purged with N₂, then sealed and microwaved for20 min at 150° C. After reaction was complete, organic layer wasseparated, filtered trough silica gel plug, concentrated and wassubjected to reverse-phase HPLC purification (RP—C₁₈, 2-50% CH₃CN/0.1%aq. TFA gradient over 13 min, 35 mL/min) to yield compound no. 58. ¹HNMR (400 MHz, DMSO-d₆) δ 9.79 (s, 1H), 8.11 (d, J=8.4 Hz, 1H), 7.53 (d,J=1.9 Hz, 1H), 7.52 (d, J=8.1 Hz, 2H), 7.39 (d, J=1.5 Hz, 1H), 7.26 (d,J=8.0 Hz, 2H), 4.14 (s, 4H), 4.06 (q, J=7.1 Hz, 2H), 3.58 (m, 3H), 3.19(q, J=11.1 Hz, 2H), 2.85 (bs, 2H), 2.34 (s, 3H), 2.29-2.23 (m, 5H), 2.09(d, J=12.9 Hz, 2H), 1.96 (d, J=13.9 Hz, 2H), 1.67-1.57 (m, 2H), 1.20 (t,J=7.1 Hz, 311). LC/MS (RP—C₁₈, 10-99% CH₃CN/0.05% TFA gradient over 5min): m/z 476.2 [M+H]⁺, retention time 2.36 min.

EXAMPLE 10

1.0 eq of the amine hydrochloride 10a (416 mg, 1.46 mmol) was suspendedin anhydrous 1,2-dichloroethane: 1,2-dimethoxyethane (6.0 mL, 1:1 v/v)and treated with 1.0 eq triethylamine (148 mg), followed by 1.5 eqtert-butyl 4-oxoazepane-1-carboxylate (467 mg, 2.19 mmol) and 3.0 eqtitanium tetraisopropoxide (1.3 mL, 1.26 g, 4.4 mmol). The reaction vialwas flushed with nitrogen and stirred at room temperature for 3 days.The reaction was diluted with methanol (6.0 mL), cooled in an ice-H₂Obath and treated with sodium borohydride (110 mg, 2.92 mmol). Thereaction was slowly warmed to room temperature and stirred thereafterfor 90 min. The reaction was then further diluted with methanol (10 mL),quenched with 1.0 N NaOH (5.0 mL) and stirred vigorously at roomtemperature for 10 min. The suspension obtained was centrifuged (3K rpm,10 min) and the supernatant concentrated under reduced pressure. Theresidue obtained was dissolved in dichloromethane (75 mL) and washedsuccessively with H₂O, saturated sodium bicarbonate, and saturatedbrine, then dried over Na₂SO₄ and filtered. The filtrate wasconcentrated in vacuo to afford 704 mg crude product 10b as a viscous,pale yellow oil. The crude product was used in the next step withoutfurther purification. t_(R)=2.14 min [10-99% CH₃CN gradient over 5 minswith 0.1% TFA (aq)]; Theoretical (M+H)⁺ m/z for C₂₅H₃₆FN₃O₃=446.3; Found446.4.

The Boc-protected amine 10b (573 mg) was dissolved in dichloromethane (5mL), cooled in an ice-H₂O bath and treated slowly with ice-coldtrifluoroacetic acid (5 mL). The reaction was stirred at ˜0° C. for 1 h,then concentrated under reduced pressure. The oil obtained was dissolvedin acetonitrile and re-concentrated under reduced pressure. The crudeTFA salt was dissolved in methanol (6.0 mL) and purified byreverse-phase HPLC (2-25% CH₃CN/0.1% TFA gradient over 10 min, 6×1.0 mLinjected, 35 mL/min). The combined pure fractions were concentrated invacuo to afford 291 mg amine 10c as the di-TFA salt, as a viscous,colorless oil. Yield (over 2 steps)=35%. ¹H-NMR (400 MHz, DMSO-d₆) δ9.83 (br s, 1H), 8.74 (br s, 2H), 8.06 (dd, J=8.8 Hz, 5.0 Hz, 1H), 7.06(br m, 1H), 6.97 (br m, 1H), 4.12 (s, 2H), 3.59 (br s, 1H), 3.13 (br m,6H), 2.36 (m, 1H), 2.20 (s, 3H), 2.13 (m, 5H), 1.89 (m, 5H), 1.71 (m,1H); t_(R)=1.06 min [10-99% CH₃CN gradient over 5 min with 0.1% TFA(aq)]; Theoretical (M+H)⁺ m/z for C₂₀H₂₈FN₃O=346.2; Found 346.0.

Deprotected amine 10c (46 mg, 0.080 mmol, di-TFA salt) was dissolved inanhydrous acetonitrile (750 μL) and treated with 3.0 eq triethylamine(24 mg, 0.24 mmol). The mixture was then treated with ethylchloroformate (9 μL, 10 mg, 0.096 mmol) and stirred at room temperaturefor 30 min. The reaction was quenched with methanol (500 μL) andpurified by reverse-phase HPLC to provide compound no. 308 (2-40%CH₃CN/0.1% TFA gradient over 10 min, 1.0 mL injected, 35 mL/min).t_(R)=1.90 min [10-99% CH₃CN gradient over 5 min with 0.1% TFA (aq)];Theoretical (M+H)⁺ m/z for C₂₃H₃₂FN₃O₃=418.2; Found 418.4.

EXAMPLE 11

Spiroindoline 11a (300.0 mg; 1.21 mmol) and 4-oxocyclohexanespirodioxolane (283.1 mg; 1.81 mmol) were dissolved in DCE (5 mL). After10 min, NaBH(OAc)₃ (512.1 mg; 2.42 mmol) was added, followed by AcOH(69.7 uL; 72.5 mg; 1.208 mmol) and the mixture was allowed to stir atroom temperature for 75 h. The reaction was quenched by adding MeOH (10mL) and was allowed to stir for 24 h. The resulting suspension wasdiluted with DCM (30 mL) and NaOH 1 N (5 mL) was added. The layers wereseparated, and the aqueous layer was extracted with DCM (3×30 mL). Thecombined organic extracts were dried on Na₂SO₄ and concentrated. Thewhite solid residue was suspended in ether, the ethereal suspension wasfiltered and the precipitate was washed with ether (3×20 mL) and driedto provide the acetate salt of the desired product 11b (400 mg, 74%yield). The material was used for the next step without furtherpurification. LC/MS m/z 389.2 [M+H]⁺, retention time 1.73 min (10-99%CH₃CN—H₂O gradient with 0.03% TFA, 5 min). ¹H NMR (400 MHz, DMSO-d₆) δ1.49 (m, 4H), 1.60 (d, J=13.0 Hz, 2H), 1.72 (d, J=9.4 Hz, 4H), 1.81 (td,J=13.4, 2.5 Hz, 2H), 2.19 (s, 3H), 2.28 (t, J=11.5 Hz, 2H), 2.37 (m,1H), 2.80 (d, J=11.5 Hz, 2H), 3.85 (t, J=2.3 Hz, 4H), 3.95 (s, 2H), 6.97(td, J=8.3, 1.8 Hz, 1H), 7.18 (dd, J=8.8, 2.7 Hz, 1H), 8.02 (dd, J=8.8,5.0 Hz, 1H)

The ketal 11b (350.0 mg; 0.82 mmol) was dissolved in 80% aq. acetic acid(20 mL) and the solution was refluxed overnight. LC/MS analysis showscomplete deprotection of the ketal, along with some deacetylation of theindoline nitrogen. The reaction mixture was diluted with water (20 mL),cooled on an ice bath and neutralized by addition of solid KOH. Theresulting suspension was filtered and the precipitate was washed withwater (3×10 mL) and dried to provide the crude product as a tan powder.This material was dissolved in DCM (10 mL) and treated with excess AcCl(1 mL) and triethylamine (1 mL). After stirring at room temperature for3 h, the mixture was diluted with DCM (30 mL) and washed with saturatedNaHCO₃. The organic layer was dried on Na₂SO₄ and concentrated toprovide the product 11c as a yellow oil (253 mg, 89% yield), which wasused for the next step without further purification. LC/MS m/z 345.0[M+H]⁺, retention time 1.43 min (10-99% CH₃CN—H₂O gradient with 0.03%TFA, 5 min); ¹H NMR (400 MHz, CDCl₃) δ 1.68 (d, J=13.3 Hz, 2H), 1.82 (m,2H), 1.91 (m, 2H), 2.07 (m, 2H), 2.18 (s, 3H), 2.29 (m, 6H), 2.45 (m,2H), 2.78 (t, J=9.5 Hz, 1H), 2.97 (d, J=11.6 Hz, 2H), 3.81 (s, 2H) 6.88(m, 2H), 8.16 (dd, J=8.5, 4.8 Hz, 1H).

The crude ketone 11c (100.0 mg; 0.29 mmol) was dissolved in pyridine (1mL) and treated with O-ethyl hydroxylamine hydrochloride (21.3 mg; 0.35mmol). The vial was sealed and heated to 60° C. for 1 h. The solvent wasevaporated under reduced pressure and the residue was dissolved in DMSO(2 mL) and the product oxime compound no. 86 purified by reverse phaseHPLC (2-99% CH₃CN—H₂O gradient with 0.03% TFA, 15 min. run). LC/MS m/z388.4 [M+H]⁺, retention time 1.87 min (10-99% CH₃CN—H₂O gradient with0.03% TFA, 5 min); ¹H NMR (free base, 400 MHz, CDCl₃) δ 1.25 (t, J=7.0Hz, 3H), 1.55 (m, 2H), 1.71 (d, J=13.1 Hz, 2H), 1.94 (m, 5H), 2.14 (m,1H), 2.25 (s, 3H), 2.30 (td, J=11.9, 5.6 Hz, 2H), 2.50 (d, J=14.3 Hz,1H), 2.62 (t, J=9.6 Hz, 1H), 2.94 (d, J=11.8 Hz, 2H), 3.25 (d, J=14.7Hz, 1H), 3.86 (s, 2H), 4.07 (q, J=7.0 Hz, 2H), 6.88 (m, 2H), 8.16 (dd,J=8.5, 4.8 Hz, 1H).

EXAMPLE 12

The N-Boc protected indanone 12a (6.5 g, 21.6 mmol),(S)-1-phenylethanamine (2.875 g, 23.72 mmol, 1.1 eq), and anhydrousZnCl₂ (88 mg, 0.647 mmol, 0.03 eq) were brought up in 35 mL dry toluenein a 100-mL flask under N₂ atmosphere. The flask was fitted with aDean-Stark trap and reflux condenser for the removal of water. Thereaction mixture was heated at reflux for 18 h. The reaction mixture wascooled, diluted with EtOAc (200 mL), and washed with 0.1 N NaOH (2×30mL), 20% saturated NH₄Cl (1×100 mL), and brine (1×100 mL). The organiclayer was then dried over Na₂SO₄, filtered, and dried down to affordimine (S)-12b as a light orange solid. LC/MS analysis of the crudeproduct indicated complete conversion to the desired product. LC/MS(10-99%) m/z 405.2 [M+H]⁺, retention time 2.76 min.

The crude imine (S)-12b (21.6 mmol) was dissolved in anhydrous MeOH (30mL) and cooled to −40° C. under N₂ atmosphere. NaBH₄ (816 mg, 21.6 mmol,1.0 eq) was added in one portion. The reaction mixture was allowed towarm to −20° C. over 2 h, then warmed to −5° C. for 3 h. The reactionmixture was then diluted with EtOAc (200 mL), then washed with 50%saturated NaHCO₃ (100 mL), water (2×100 mL), and brine (100 mL). Theorganic layer was dried over Na₂SO₄, filtered, and dried down to yield(S, S)-12c as a colorless oil. The oil was brought up in anhydrousdiethyl ether, and 1 eq of ethereal HCl was added to precipitate theproduct as a fine white solid. The solid was filtered, washed with ether(100 mL), and dried under vacuum to obtain 7.2 of (S, S)-12c HCl salt asa white powder (75% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 10.08 (m, 1H),9.49 (m, 1H), 8.01 (d, J=7.5 Hz, 1H), 7.77 (d, J=7.1 Hz, 2H), 7.29-7.47(m, 6H), 4.91 (m, 1H), 4.62 (m, 1H), 3.94 (m, 2H), 2.87 (bs, 2H), 2.62(dd, J=13.5, 8.0 Hz, 1H), 1.99 (dd, J=13.5, 7.5 Hz, 1H), 1.92 (dt,J=12.9, 4.4 Hz, 1H), 1.76 (d, J=6.7 Hz, 3H), 1.58 (d, J=12.9 Hz, 1H),1.42 (s+obscured m, 11H); LC/MS (10-99%) m/z 407.4 [M+H]⁺, retentiontime 2.70 min.

(S, S)-12c (3.0 g, 6.8 mmol), ammonium formate (8.5 g, 135.4 mmol, 20eq), and 800 mg 10% Pd/C (wet, 50% by weight) were brought up in MeOH(30 mL) in a 100-mL flask fixed with a N₂ balloon. The mixture wasstirred at room temperature for 28 h. The reaction mixture filteredthrough packed Celite and concentrated in vacuo to ˜10 mL. Theconcentrate was diluted with 50% saturated NaHCO₃ (200 mL), and theproduct extracted into EtOAc (3×100 mL). The combined extracts werewashed with brine (50 mL), dried over Na₂SO₄, and concentrated in vacuoto obtain (S)-12d as a colorless oil (2.0 g, 98% yield). ¹H NMR (400MHz, DMSO-d₆) δ 7.34 (m, 1H), 7.02-7.21 (m, 3H), 4.23 (t, J=7.7 Hz, 1H),3.99 (m, 2H), 2.90 (br s, 2H), 2.57 (dd, J=12.7, 7.3 Hz, 1H), 2.00 (bs,2H), 1.92 (dt, J=12.9, 4.5 Hz 1H), 1.42 (s+obscured m, 13H); LC/MS(10-99%) m/z 303.2 [M+H]⁺, 286.2 [m/z —NH₃]⁺, retention time 2.31 min.

(S)-12d (300 mg, 0.99 mmol) was dissolved in 1.5 mL anhydrous CH₃CN andcooled to 0° C., followed by ethyl chloroformate (118 mg, 1.09 mmol, 1.1eq) and triethylamine (200 μL). White precipitate formed upon additionof the triethylamine. The reaction was allowed to warm to roomtemperature and then stirred for 1 h. The reaction mixture was dilutedwith EtOAc (30 mL) and washed with 50% saturated NaHCO₃ (20 mL), water(20 mL), and brine (20 mL). The solution was dried over Na₂SO₄,filtered, and dried in vacuo to obtain product (S)-12e as a light yellowoil (>90% pure). LC/MS (10-99%) m/z 375.2 [M+H]⁺, retention time 3.43min.

The crude (S)-12e was dissolved 5 mL CH₂Cl₂ and cooled to 0° C.,followed by the addition of 5 mL TFA. The reaction mixture was stirredat 0° C. for 1 h, diluted with CH₃CN (20 mL), and dried in vacuo toobtain the (S)-12f TFA salt. The oil was dissolved in CH₂Cl₂ (30 mL),washed with 0.1 N NaOH (2×10 mL), brine (10 mL), dried over Na₂SO₄,filtered, and dried in vacuo to obtain the product (S)-12f as a lightyellow oil (269 mg, 98% yield over 2 steps). LC/MS (10-99%) m/z 275.2[M+H]⁺, retention time 1.42 min.

(S)-12f (269 mg, 0.98 mmol) was dissolved in cold DCE (1.5 mL) andtreated with (1S,2S,4S)-bicyclo[2.2.1]hept-5-ene-2-carbaldehyde (119 mg,0.98 mmol, 1.0 eq), followed by portion-wise addition of NaBH(OAc)₃ (300mg, 1.4 mmol, 1.4 eq). The reaction was allowed to stir at roomtemperature for 1 h and was then quenched with MeOH (1 mL) and allowedto stir for another 30 min (until gas evolution stopped). The crudereaction mixture was purified by HPLC (10-99 CH₃CN gradient, 0.05% TFA)to provide the desired product (S)-12 g as the TFA salt. LC/MS (10-99%)m/z 381.2 [M+H]⁺, retention time 2.28 min.

The combined HPLC fractions (˜10 mL) were treated with 10% Pd/C (50 mg,wet, 50% by weight) under H₂ atmosphere with to cleanly provide (S)-12 gafter 2 h of rapid stirring at room temperature. The solution wasfiltered through a 0.2 micron nylon filter and concentrated to provide114 mg of compound no. 274 TFA salt (23% over 2 steps). LC/MS (10-99%)m/z 383.2 [M+H]⁺, retention time 2.28 min; ¹H-NMR (HCl salt, 400 MHz,DMSO-d₆) δ 10.39 (br s, 1H), 7.55 (d, J=8.4 Hz, 1H), 7.25 (m, 4H), 5.11(m, 1H), 4.06 (q, J=7.0 Hz, 2H), 3.45 (m, 2H), 3.09 (m, 4H), 2.64 (m,2H), 2.33 (br s, 2H), 2.15 (m, 2H), 1.84 (m, 1H), 1.67 (m, 3H), 1.48 (m,2H), 1.34 (m, 3H), 1.20 (t, J=7.1 Hz, 3H), 1.14 (m, 1H), 0.88 (m, 1H).

Spiroindane (R)-compound no. 274 was produced utilizing an analogoussynthetic route with the substitution of (R)-1-phenylethanamine for(S)-1-phenylethanamine in the synthesis of intermediate imine 12b (step1).

EXAMPLE 13

To a flask containing (S, S)-13a (See Example 12, 1.5 g, 3.39 mmol) andK₂CO₃ (1.87 g, 13.54 mmol, 4 eq) was added 2 mL anhydrous DMF followedby 8 mL anhydrous THF. The mixture was treated with MeI (2.40 g, 16.93mmol, 5 eq) and heated to 45° C. for 6 h, followed by stirring at roomtemperature for 16 h. The reaction mixture was diluted with EtOAc (200mL) and washed with 20% saturated NH₄Cl (50 mL), 50% saturated NaHCO₃(50 mL), brine (50 mL). The solution was dried over Na₂SO₄, filtered,and dried in vacuo to yield a reddish oil. The oil was dissolved indiethyl ether and filtered to remove insoluble material, followed bytreatment with 1 eq of ethereal HCl. The resulting solution was drieddown in vacuo to yield crude (S)-13b as a light orange solid. LC/MS(10-99%) m/z 421.0 [M+H]⁺, retention time 2.77 min.

Crude (S)-13b was dissolved in CH₂Cl₂ (50 mL) and cooled to −10° C.,followed by the addition of 10 mL TFA. The reaction mixture was stirredat −10° C. for 1 h, diluted with CH₃CN (20 mL), and dried in vacuo toobtain the (S)-13c TFA salt. The oil was dissolved in CH₂Cl₂ (30 mL),washed with 50% saturated NaHCO₃ (2×10 mL), brine (10 mL), dried overNa₂SO₄, filtered, and dried in vacuo to obtain the product (S)-13c as acolorless oil (673 mg, 67% yield over 2 steps). ¹H NMR (400 MHz,DMSO-d₆) δ 7.46 (d, J=7.2 Hz, 2H), 7.34 (t, J=7.4 Hz, 2H), 7.16-7.25 (m,5H), 4.66 (t, J=8.0 Hz, 1H), 3.79 (q, J=6.7 Hz, 1H), 2.99 (app t, J=12.0Hz, 2H), 2.79 (dt, J=12.4, 2.5 Hz, 1H), 2.69 (dt, J=12.7, 2.3 Hz, 1H),2.07 (q, J=8.0 Hz, 1H), 1.97 (dt, J=13.3, 4.2 Hz, 1H), 1.85 (s, 3H),1.73 (m, 1H), 1.52 (dt, J=12.7, 4.2 Hz, 1H), 1.42 (d, J=6.6 Hz, 3H),1.36 (app t, J=12.9 Hz, 3H); LC/MS (10-99%) m/z 321.2 [M+H]⁺, retentiontime 1.60 min.

(S)-13c (650 mg, 2.03 mmol) and(1S,2S,4S)-bicyclo[2.2.1]hept-5-ene-2-carbaldehyde (262 mg, 2.15 mmol)were dissolved in DCE (13 mL) and the mixture cooled to −30° C.,followed by portion-wise addition of NaBH(OAc)₃ (646 mg, 3.05 mmol). Thereaction was stirred at −30° C. for 2 h and was the allowed to come toroom temperature and stirred for 16 h. The reaction was quenched withMeOH (5 mL) and diluted with EtOAc (200 mL). The crude reaction waswashed with 50% saturated NaHCO₃ (50 mL), water (50 mL), and brine (50mL). The organic layer was dried over Na₂SO4, filtered and dried invacuo to yield the product (S)-13d as a colorless oil (802 mg, 93%yield).

(S)-13d (800 mg, 6.8 mmol), ammonium formate (2.36 g, 37.5 mmol), and800 mg 10% Pd/C (wet, 50% by weight) were brought up in MeOH (8 mL) in a25-mL flask fixed with a N₂ balloon. The mixture was stirred at roomtemperature for 24 h. 1.18 g of ammonium formate were added and themixture stirred for an additional 24 h. The reaction mixture wasfiltered through packed Celite, diluted with 50% saturated NaHCO₃ (200mL), and the product (S)-13e extracted into EtOAc (5×75 mL). Thecombined extracts were washed with brine (50 mL), dried over Na₂SO₄, andconcentrated in vacuo to obtain (S)-13e as a colorless oil (493 mg, 81%yield). LC/MS (10-99%) m/z 325.4 [M+H]⁺, retention time 1.52 min.

(S)-13e (123 mg, 0.38 mmol) was dissolved in 1.5 mL anhydrous CH₃CN andcooled to 0° C., followed by the additional of acetyl chloride (33 mg,0.42 mmol) and triethylamine (200 μL). White precipitate formed uponaddition of the triethylamine. The reaction was allowed to warm to roomtemperature and then stirred for 1 h. The crude reaction mixture waspurified by HPLC (10-99 CH₃CN gradient, 0.05% TFA) to provide thedesired compound no. 190 as the TFA salt (65 mg, 47% yield). LC/MS(10-99%) m/z 367.2 [M+H]⁺, retention time 1.99 min.

Spiroindane (R) form of compound no. 190 was produced utilizing ananalogous synthetic route with the substitution of(R)-1-phenylethanamine for (S)-1-phenylethanamine in the synthesis ofintermediate 13a (See Example 12).

EXAMPLE 14

Intermediate 14a (49 mg; 0.2 mmol) and4-formyl-4-methylpiperidine-1-carboxylate (40 mg; 0.2 mmol) weredissolved in DCE (2 mL) and NaBH(OAc)₃ (85 mg; 0.4 mmol) was added. Thereaction was stirred at room temperature for 20 hours. The reaction wasdiluted with DCM (10 mL) and 1N HCl (20 mL), the layers were separated,and the organic layer was discarded. The aqueous layer was washed withDCM (10 mL) and then was basified with NaOH. The aqueous layer was thenwashed with EtOAc (3×20 mL) and the combined organic layers were driedover Na₂SO₄, filtered, and concentrated under high vacuum. The crudeproduct compound no. 314 was purified using reversed-phasechromatography (2-99% CH₃CN/H₂O gradient with 0.05% TFA). LC/MS m/z[M+H]+428.2, retention time 1.85 min (10-99% CH₃CN—H₂O gradient with0.03% TFA, 5 min); ¹H-NMR (400 MHz, DMSO-d₆) δ 8.50 (br s, 1H), 8.26 (d,J=8.2 Hz, 1H), 7.27 (m, 4H), 5.35 (m, 1H), 4.04 (q, J=7.1 Hz, 2H), 3.69(m, 2H), 3.53 (m, 2H), 3.31 (m, 2H), 3.18 (m, 5H), 2.69 (m, 1H), 2.07(m, 1H), 1.89 (s, 3H), 1.66 (m, 3H), 1.50 (m, 4H), 1.19 (overlapping qand s, 6H).

EXAMPLE 15

The mixture of N-Boc protected spiroindanone 15a (20 g, 66.4 mmol) andMeOH/HCl (2.5 mol/L, 100 mL) were stirred overnight. After evaporationthe residue was washed by petroleum ether to gave the correspondingamine hydrochloride 15b (15.4 g, 97.6%).

To a solution of compound 15b (5.0 g, 24.84 mmol) and Et₃N (7.54 g,74.53 mol) in CH₂Cl₂ (50 mL) was added drop-wise Cbz-Cl (4.66 g, 27.33mmol) at 0° C. The reaction was allowed to warm to room temperature andstirred overnight. The precipitate was filtered, washed with Et₂O anddried to furnish compound 15c (6.1 g, yield 99%).

A solution of compound 15c (3 g, 10.3 mmol) in EtOH (30 mL) containingNH₂OH.HCl (1.43 g, 20.6 mmol) and NaOAc (1.52 g, 18.53 mmol) was heatedunder reflux for 1.5 h. The solvent was removed by evaporation and theresidue was partitioned between CH₂Cl₂ and water. The organic phase waswashed with brine, dried over Na₂SO₄, and concentrated to give compound15d (3.14 g, yield 99%), which could be used directly in the next step.

2,4,6-trichloro-[1,3,5]-triazine (1.32 g, 7.16 mmol) was added to DMF(9.6 mL) maintained at 25° C. The reaction was monitored by TLC untilTCT was consumed. Then compound 15d (1.6 g, 4.77 mmol) in DMF (17 mL)was added. After the addition, the mixture was stirred at roomtemperature overnight. Water was added. The mixture was extracted withEtOAc. The combined organic layers were washed with sat. Na₂CO₃,followed by 1N HCl and brine, dried over Na₂SO₄ and concentrated. Theresidue was purified by prep HPLC to obtain compound 15e (260 mg, yield16%).

The mixture of compound 15e (1.2 g, 3.4 mmol) and Pd/C (200 mg) in MeOH(20 mL) was hydrogenated under atmosphere pressure at room temperaturefor 3 h. The catalyst was filtered and the filtrate was concentratedunder reduced pressure. The residue was purified by preparative HPLCtwice to give 15f (110 mg, 11%) as a TFA salt. ¹H NMR (CDCl₃) δ 7.65 (d,J=7.5 Hz, 1H), 7.29-7.45 (m, 3 H), 3.45 (d, J=12.3 Hz, 2H), 3.20 (t,J=12.3 Hz, 2 H), 2.96 (s, 2 H), 2.10-2.21 (m, 2H), 1.70 (d, J=14.1 Hz,2H). MS (ESI) m/z 217.06 [M+H]⁺.

Amine 15f (22 mg, 0.1 mmol) and ethyl 4-formylpiperidine-1-carboxylate(28 mg, 0.15 mmol) were dissolved in DCE (1 mL) and NaBH(OAc)₃ (42 mg;0.2 mmol) was added. The reaction was stirred at room temperature for 16h. The reaction was diluted methanol (0.5 mL), filtered, and compoundno. 34 was purified using reversed-phase chromatography (10-99%CH₃CN/H₂O gradient with 0.05% TFA). LC/MS m/z 386.2 [M+H]⁺, retentiontime 2.05 min (10-99% CH₃CN—H₂O gradient with 0.03% TFA, 5 min); ¹H NMR(free base, 400 MHz, DMSO-d₆) δ 7.71 (d, J=3.9 Hz, 2H), 7.61 (d, J=7.6Hz, 1H), 7.47-7.41 (m, 1H), 4.05-3.96 (m, 4H), 2.86-2.67 (m, 4H), 2.56(d, J=9.7 Hz, 2H), 2.18 (s, 2H), 2.01 (d, J=7.7 Hz, 4H), 1.73 (d, J=11.1Hz, 4H), 1.45 (d, J=8.7 Hz, 2H), 1.18 (t, J=7.1 Hz, 3H), 1.03-0.96 (m,2H).

EXAMPLE 16

A stirred mixture of sodium hydride (60%, 31 g, 0.79 mol) in dry xylene(500 mL), under a nitrogen atmosphere, was heated to reflux for 30 min.1,3-Dihydro-indol-2-one 16a (100 g, 0.75 mol) was then slowly added viaan addition funnel and stirred at reflux for 1.5 hrs. Dimethyl sulfate(104 g, 0.83 mol) was added drop-wise, whereupon the resultinghomogeneous solution was refluxed for an additional 2 hrs. After coolingto room temperature, the reaction mixture was washed with water, driedover Na₂SO₄, and concentrated under reduced pressure to afford1-methyl-1,3-dihydro-indol-2-one 16b (74 g, 67.3%). ¹H NMR (300 MHz,CDCl₃) δ 7.23-7.31 (m, 2 H), 7.04 (t, J=7.5 Hz, 1 H), 6.82 (d, J=7.8 Hz,1 H), 3.52 (s, 2 H), 3.21 (s, 3H).

A suspension of NaH (60%, 70 g, 0.48 mol) in THF (300 mL) was stirredfor 10 min at 0° C. Then a solution of 1-methyl-1,3-dihydro-indol-2-one16b (70 g, 2.88 mol) in THF (200 mL) was added at 0° C., and the mixturewas stirred for 1 h at room temperature.Benzyl-bis-(2-chloro-ethyl)-amine (129 g, 0.48 mol) was added inportions at 0° C. The mixture was stirred overnight at room temperature,and then was poured into ice-water, extracted with EtOAc. The combinedorganic layers were dried over Na₂SO₄, and concentrated under reducedpressure. The residue was purified by column on silica gel (P.E./E.A.2:1) to give compound 16c (24 g, 16.3%). ¹H NMR (300 MHz, CDCl₃) δ7.25-7.42 (m, 7 H), 7.02-7.07 (m, 1 H), 6.83 (d, J=7.5, 1 H), 3.68 (s, 2H), 3.19 (s, 3 H), 2.74-2.99 (m, 2 H), 2.66-2.72 (m, 2 H), 1.93-2.01 (m,2 H), 1.79-1.85 (m, 2 H).

To a solution of compound 16c (12 g, 39.2 mmol) in MeOH (100 mL) wasadded Pd(OH)₂/C (1.5 g, 20%) under N₂. The suspension was hydrogenatedunder H₂ (50 psi) at room temperature for 4.5 hrs. The catalyst wasfiltered off, and the filtrate was concentrated under reduced pressureto give the deprotected spiroindolone product 16d (8 g, 94.5%). ¹H NMR(400 MHz, DMSO-d₆) δ 7.46 (d, J=7.2, 1 H), 7.23-7.27 (m, 1 H), 6.96-7.03(m, 2 H), 3.04-3.14 (m, 5 H), 2.83-2.89 (m, 2 H), 1.61-1.67 (m, 2 H),1.45-1.51 (m, 2 H). MS (ESI) m/z 217.1 [M+H]⁺.

1.0 eq of deprotected spiroindolone 16d (22 mg, 0.10 mmol) was dissolvedin anhydrous 1,2-dichloroethane: 1,2-dimethoxyethane (1.0 mL, 1:1 v/v)and treated with 1.5 N-Carbethoxy-4-tropinone (30 mg, 0.15 mmol),followed by titanium tetraisopropoxide (88 μL, 85 mg, 0.30 mmol). Thevial was flushed with nitrogen and stirred at room temperature ˜70 h.The reaction was then diluted with methanol (1.0 mL), cooled in anice-H₂O bath and treated with sodium borohydride (8 mg, 0.20 mmol).After warming to room temperature and stirring for 90 min, the reactionwas further diluted with methanol (2.0 mL), quenched with 1.0 N NaOH(500 μL) and stirred vigorously at room temperature for 10 min. Thesuspension obtained was centrifuged (3K rpm, 10 min) and the supernatantconcentrated under reduced pressure. The residue obtained was dissolvedin MeOH:acetonitrile (1250 μL, 1:1 v/v), filtered, and purified byreverse-phase HPLC (2-40% CH₃CN/0.1% TFA gradient over 10 min) to yieldproduct compound no. 149. LC/MS (10-99%) m/z [M+H]+398.2, retention time1.93 min.

EXAMPLE 17

Compound no. 364 was synthesized using known methods and those describedabove.

¹H NMR (400 MHz, CDCl₃) δ 1.27 (t, J=6.3 Hz, 3H), 1.56 (d, J=11.5 Hz,2H), 1.67 (q, J=7.0 Hz, 4H), 1.82 (m, 2H), 1.97 (m, 6H), 2.29 (t, J=11.5Hz, 2H), 2.82 (m, 1H), 2.89 (dd, J=13.7, 6.5 Hz, 2H), 4.13 (q, J=7.1 Hz,2H), 4.35 (d, J=24.4 Hz, 2H), 7.17 (m, 4H).

EXAMPLE 18

Compound no. 413 was synthesized using known methods and those describedabove.

¹H NMR (free base, 400 MHz, DMSO-d₆) δ 7.20-7.10 (m, 4H), 4.02 (q, J=7.1Hz, 2H), 3.99-3.96 (m, 2H), 2.84 (t, J=7.3 Hz, 2H), 2.81-2.77 (m, 4H),2.16 (d, J=4.9 Hz, 2H), 2.06 (t, J=12.2 Hz, 2H), 1.94 (t, J=7.3 Hz, 2H),1.80 (t, J=11.3 Hz, 2H), 1.74-1.70 (m, 3H), 1.43 (d, J=12.5 Hz, 2H),1.18 (t, J=7.1 Hz, 3H), 1.02-0.93 (m, 2H).

EXAMPLE 19

Compound no. 375 was synthesized using known methods and those describedabove.

¹H NMR (400 MHz, DMSO-d₆) δ 10.18 (s, 1H), 6.99 (dt, J=12.8, 4.5 Hz,1H), 6.91 (dd, J=8.0, 2.7 Hz, 1H), 6.82 (dd, J=8.7, 4.1 Hz, 1H), 6.25(q, J=2.9 Hz, 1H), 6.07 (q, J=2.7 Hz, 1H), 4.50 (s, 2H), 3.51 (t, J=13.2Hz, 2H), 3.04-2.96 (m, 3H), 2.91-2.84 (m, 2H), 2.74-2.68 (m, 1H),2.40-2.30 (m, 2H), 2.03-1.97 (m, 2H), 1.88 (d, J=14.2 Hz, 2H), 1.32 (dd,J=33.8, 7.1 Hz, 2H), 0.69 (d, J=11.4 Hz, 1H).

EXAMPLE 20

Compound no. 181 was synthesized using known methods and those describedabove.

¹H-NMR (400 MHz, DMSO-d₆) δ 10.03 (br s, 1H), 7.21 (dd, J=8.5, 2.3 Hz,1H), 7.08 (d, J=2.3 Hz, 1H), 6.85 (d, J=8.5 Hz, 1H), 4.52 (s, 2H), 3.41(m, 2H), 3.25 (m, 1H), 3.01 (m, 2H), 2.63 (m, 2H), 2.44 (m, 1H), 2.27(m, 1H), 1.86 (m, 4H), 1.51 (m, 3H), 1.39 (m, 2H), 1.24 (m, 1H).

EXAMPLE 21

Compound no. 23 was synthesized using known methods and those describedabove.

¹H-NMR (400 MHz, DMSO-d₆) δ 10.27 (br s, 1H), 8.53 (br s, 1H), 6.93 (d,J=7.9 Hz, 1H), 6.88 (s, 1H), 6.72 (d, J=7.9 Hz, 1H), 3.48 (s, 2H), 3.40(m, 3H), 3.04 (m, 2H), 2.64 (m, 1H), 2.57 (br s, 1H), 2.38 (m, 1H), 2.26(m, 1H), 2.24 (s, 3H), 1.94 (m, 2H), 1.78 (m, 2H), 1.55 (m, 3H), 1.39(m, 3H).

EXAMPLE 22

Compound no. 367 was synthesized using known methods and those describedabove.

¹H-NMR (300 MHz, CDCl₃): δ 7.08 (m, 1H), 6.95 (m, 2H), 4.28 (br s, 2H),4.09 (q, J=7.2 Hz, 2H), 3.80 (s, 2H), 3.62 (m, 2H), 3.00 (m, 2H), 2.91(m, 2H), 2.49 (m, 3H), 1.95-2.02 (m, 6H), 1.69 (m, 2H), 1.48 (m, 2H),1.25 (t, J=7.2 Hz, 3H).

EXAMPLE 23

Compound no. 370 was synthesized using known methods and those describedabove.

¹H-NMR (400 MHz, DMSO-d₆) δ 10.65 (br s, 1H), 8.05 (dd, J=8.9, 4.9 Hz,1H), 7.06 (td, J=9.0, 2.7 Hz, 1H), 6.92 (dd, J=8.3, 2.7 Hz, 1H), 4.27(br s, 2H), 4.08 (m, 4H), 3.74 (m, 1H), 3.55 (br s, 2H), 3.06 (m, 2H),2.30 (m, 2H), 2.20 (s, 3H), 2.07 (m, 2H), 1.86 (m, 6H), 1.67 (m, 2H),1.22 (t, J=7.1 Hz, 3H).

EXAMPLE 24

Compound no. 422 was synthesized using known methods and those describedabove.

¹H-NMR (400 MHz, DMSO-d₆) δ 10.61 (br s, 1H), 7.93 (d, J=8.1 Hz, 1H),7.02 (d, J=8.2 Hz, 1H), 6.96 (s, 1H), 4.06 (s, 2H), 3.96 (m, 3H), 3.59(s, 3H), 3.51 (m, 2H), 3.11 (m, 2H), 3.00 (t, J=6.0 Hz, 2H), 2.83 (br s,2H), 2.47 (m, 1H), 2.28 (s, 3H), 2.18 (s, 3H), 2.11 (m, 1H), 1.88 (m,2H), 1.77 (m, 2H), 1.13 (m, 2H).

EXAMPLE 25

Compound no. 92 was synthesized using known methods and those describedabove.

¹H-NMR (400 MHz, DMSO-d₆) δ 10.97 (br s, 1H), 7.93 (d, J=8.1 Hz, 1H),7.02 (d, J=8.2 Hz, 1H), 6.95 (s, 1H), 4.13 (m, 2H), 4.06 (m, 4H), 3.45(m, 3H), 3.12 (m, 2H), 2.83 (br s, 2H), 2.43 (m, 2H), 2.28 (s, 3H), 2.19(s, 3H), 2.17 (m, 2H), 1.82 (m, 2H), 1.64 (m, 2H), 1.20 (t, J=7.1 Hz,3H).

EXAMPLE 26

Compound no. 412 was synthesized using known methods and those describedabove.

¹H NMR (400 MHz, DMSO-d₆) δ 11.06 (s, 1H), 8.05 (q, J=4.6 Hz, 1H), 7.06(dt, J=12.9, 4.5 Hz, 1H), 6.94 (dd, J=8.3, 2.6 Hz, 1H), 4.13-4.09 (m,4H), 4.05 (q, J=7.1 Hz, 2H), 3.50-3.39 (m, 3H), 3.13 (q, J=11.4 Hz, 2H),2.83 (bs, 2H), 2.46 (t, J=13.5 Hz, 2H), 2.20 (s, 3H), 2.16 (d, J=11.6Hz, 2H), 1.88 (d, J=13.8 Hz, 2H), 1.67-1.59 (m, 2H), 1.20 (t, J=7.1 Hz,3H).

EXAMPLE 27

Compound no. 361 was synthesized using known methods and those describedabove.

¹H NMR (400 MHz, DMSO-d₆) δ 1.22 (t, J=7.2 Hz, 3H), 1.66 (d, J=6.5 Hz,2H), 1.87 (m, 6H), 2.05 (s, 2H), 2.21 (t, J=12.3 Hz, 2H), 2.87 (s, 6H),3.05 (m, 2H), 3.52 (d, J=11.6 Hz, 2H), 3.73 (m, 1H), 3.84 (s, 2H), 4.08(q, J=7.1 Hz, 2H), 4.26 (s, 2H), 6.90 (dd, J=8.3, 2.4 Hz, 1H), 7.00 (m,2H), 10.38 (br s, 1H).

Example 28

Compound no. 39 was synthesized using known methods and those describedabove.

¹H NMR (400 MHz, CD₃CN) δ 1.25 (t, J=7.1 Hz, 3H), 1.66 (qd, J=12.3, 4.5Hz, 2H), 1.98 (s, 2H), 2.10 (d, J=11.8 Hz, 2H), 2.28 (td, J=14.2, 3.7Hz, 2H), 2.81 (t, J=15.9 Hz, 2H), 2.92 (s, 6H), 3.08 (q, J=11.3 Hz, 2H),3.38 (dd, J=13.4, 10.5 Hz, 1H), 3.52 (d, J=12.3 Hz, 2H), 3.87 (s, 2H),4.11 (q, J=7.1 Hz, 2H), 4.26 (d, J=12.1 Hz, 2H), 6.97 (m, 3H).

EXAMPLE 29

Compound no. 91 was synthesized using known methods and those describedabove.

¹H NMR (400 MHz, CD₃CN) δ 0.96 (t, J=7.4 Hz, 3H), 1.66 (m, 4H), 1.98 (s,2H), 2.10 (d, J=11.3 Hz, 2H), 2.28 (dt, J=19.9, 7.2 Hz, 2H), 2.87 (br s,2H), 2.92 (s, 6H), 3.08 (q, J=11.2 Hz, 2H), 3.38 (t, J=12.2 Hz, 1H),3.52 (d, J=11.9 Hz, 2H), 3.87 (s, 2H), 4.02 (t, J=6.6 Hz, 2H), 4.27 (d,J=12.8 Hz, 2H), 6.97 (m, 3H).

EXAMPLE 30

Compound no. 54 was synthesized using known methods and those describedabove.

¹H NMR (400 MHz, CD₃CN) δ 1.24 (d, J=6.2 Hz, 6H), 1.65 (dq, J=12.3, 4.5Hz, 2H), 1.99 (s, 2H), 2.09 (d, J=11.9 Hz, 2H), 2.25 (td, J=14.2, 3.7Hz, 2H), 2.81 (t, J=11.4 Hz, 2H), 2.93 (s, 6H), 3.09 (q, J=11.3 Hz, 2H),3.39 (m, 1H), 3.52 (d, J=12.3 Hz, 2H), 3.87 (s, 2H), 4.26 (d, J=12.8 Hz,2H), 4.86 (heptet, J=6.2 Hz, 1H), 6.98 (m, 3H).

EXAMPLE 31

Compound no. 208 was synthesized using known methods and those describedabove.

¹H NMR (400 MHz, CD₃CN) δ 1.67 (dq, J=12.2, 4.2 Hz, 2H), 2.15 (m, 4H),2.27 (t, J=14.2 Hz, 2H), 2.87 (br s, 2H), 2.92 (s, 6H), 3.09 (q, J=11.3Hz, 2H), 3.39 (t, J=12.0 Hz, 1H), 3.52 (d, J=12.0 Hz, 2H), 3.82 (m, 6H),3.87 (s, 2H), 4.25 (d, J=11.2 Hz, 2H), 5.19 (s, 1H), 6.96 (m, 3H).

EXAMPLE 32

Compound no. 120 was synthesized using known methods and those describedabove.

¹H NMR (400 MHz, CD₃CN) δ 1.67 (dq, J=12.2, 4.2 Hz, 2H), 2.15 (m, 4H),2.27 (t, J=14.2 Hz, 2H), 2.87 (br s, 2H), 2.92 (s, 6H), 3.09 (q, J=11.3Hz, 2H), 3.39 (t, J=12.0 Hz, 1H), 3.52 (d, J=12.0 Hz, 2H), 3.82 (m, 6H),3.87 (s, 2H), 4.25 (d, J=11.2 Hz, 2H), 5.19 (s, 1H), 6.96 (m, 3H).

EXAMPLE 33

Compound no. 48 was synthesized using known methods and those describedabove.

¹H NMR (400 MHz, CD₃CN) δ 1.69 (dq, J=12.3, 4.1 Hz, 2H), 1.99 (s, 2H),2.12 (d, J=11.5 Hz, 2H), 2.28 (t, J=14.1 Hz, 2H), 2.87 (brs, 2H), 2.92(s, 6H), 3.09 (q, J=11.3 Hz, 2H), 3.40 (t, J=11.9 Hz, 1H), 3.52 (d,J=12.3 Hz, 2H), 3.87 (s, 2H), 4.27 (m, 3H), 4.34 (m, 1H), 4.56 (t, J=3.9Hz, 1H), 4.68 (t, J=3.9 Hz, 1H), 6.97 (m, 3H).

EXAMPLE 34

Compound no. 352 was synthesized using known methods and those describedabove.

¹H NMR (400 MHz, CD₃CN) δ 1.68 (qd, J=12.3, 4.5 Hz, 2H), 1.85 (t, J=2.3Hz, 3H), 1.98 (s, 2H), 2.12 (d, J=12.1 Hz, 2H), 2.30 (td, J=14.1, 3.7Hz, 2H), 2.87 (br s, 2H), 2.92 (s, 6H), 3.08 (q, J=11.0 Hz, 2H), 3.39(t, J=12.1 Hz, 1H), 3.51 (d, J=11.8 Hz, 2H), 3.87 (s, 2H), 4.25 (br s,2H), 4.65 (d, J=2.1 Hz, 2H), 6.98 (m, 3H).

EXAMPLE 35

Compound no. 127 was synthesized using known methods and those describedabove.

¹H NMR (400 MHz, CD₃CN) δ 1.68 (qd, J=12.3, 4.4 Hz, 2H), 1.99 (s, 2H),2.11 (d, J=12.3 Hz, 2H), 2.27 (m, 2H), 2.55 (td, J=6.6, 2.7 Hz, 2H),2.85 (br s, 2H), 2.92 (s, 6H), 3.08 (q, J=11.1 Hz, 2H), 3.39 (t, J=11.9Hz, 1H), 3.51 (d, J=12.4 Hz, 2H), 3.87 (s, 2H), 4.15 (t, J=6.6 Hz, 2H),4.26 (d, J=13.2 Hz, 2H), 6.97 (m, 3H).

EXAMPLE 36

Compound no. 264 was synthesized using known methods and those describedabove.

¹H NMR (400 MHz, CD₃CN) δ 1.67 (qd, J=12.3, 4.3 Hz, 2H), 1.99 (s, 2H),2.11 (d, J=10.6 Hz, 2H), 2.29 (t, J=14.1 Hz, 2H), 2.87 (br s, 2H), 2.92(s, 6H), 3.08 (q, J=10.9 Hz, 2H), 3.34 (s, 3H), 3.40 (t, J=6.6 Hz, 1H),3.52 (d, J=6.3 Hz, 2H), 3.57 (t, J=4.6 Hz, 2H), 3.86 (s, 2H), 4.18 (dd,J=5.1, 4.0 Hz, 2H), 4.26 (d, J=12.7 Hz, 2H), 6.96 (m, 3H).

EXAMPLE 37

Compound no. 172 was synthesized using known methods and those describedabove.

¹H NMR (400 MHz, CD₃CN) δ 1.71 (qd, J=12.3, 4.4 Hz, 2H), 1.99 (s, 2H),2.14 (d, J=14.4 Hz, 2H), 2.22 (s, 3H), 2.35 (td, J=14.2, 3.4 Hz, 2H),2.89 (br s, 2H), 3.10 (q, J=10.6 Hz, 2H), 3.41 (t, J=11.4 Hz, 1H), 3.53(d, J=12.6 Hz, 2H), 4.06 (s, 2H), 4.28 (m, 2H), 4.35 (t, J=4.0 Hz, 1H),4.57 (t, J=4.0 Hz, 1H), 4.69 (t, J=4.0 Hz, 1H), 7.01 (m, 2H), 8.14 (dd,J=8.8, 4.9 Hz, 1H).

EXAMPLE 38

Compound no. 102 was synthesized using known methods and those describedabove.

¹H NMR (400 MHz, CD₃CN) δ 1.71 (qd, J=12.3, 4.4 Hz, 2H), 1.85 (t, J=2.4Hz, 3H), 1.99 (s, 2H), 2.13 (d, J=12.2 Hz, 2H), 2.22 (s, 3H), 2.35 (td,J=14.1, 3.6 Hz, 2H), 2.88 (br s, 2H), 3.09 (q, J=11.2 Hz, 2H), 3.40 (t,J=12.0 Hz, 1H), 3.53 (d, J=12.7 Hz, 2H), 4.06 (s, 2H), 4.26 (br s, 2H),4.66 (d, J=2.2 Hz, 2H), 6.99 (td, J=9.0, 2.7 Hz, 1H), 7.05 (dd, J=8.6,2.6 Hz, 1H), 8.14 (dd, 8.7, 4.8, 1H).

EXAMPLE 39

Compound no. 62 was synthesized using known methods and those describedabove.

¹H NMR (400 MHz, CD₃CN) δ 1.70 (qd, J=12.2, 4.3 Hz, 2H), 1.99 (s, 2H),2.13 (d, J=11.1 Hz, 2H), 2.22 (s, 3H), 2.27 (t, J=2.6 Hz, 1H), 2.36 (td,J=14.0, 3.5 Hz, 2H), 2.55 (td, J=6.6, 2.7 Hz, 2H), 2.87 (br s, 2H), 3.09(q, J=10.4 Hz, 2H), 3.40 (t, J=12.1 Hz, 1H), 3.53 (d, J=12.3 Hz, 2H),4.06 (s, 2H), 4.16 (t, J=6.6 Hz, 2H), 4.28 (d, J=12.6 Hz, 2H), 6.99 (td,J=9.0, 2.6 Hz, 1H), 7.05 (dd, J=8.6, 2.6 Hz, 1H), 8.13 (dd, J=8.8, 4.9Hz, 1H).

EXAMPLE 40

Compound no. 32 was synthesized using known methods and those describedabove.

¹H NMR (400 MHz, CD₃CN) δ 1.72 (d, J=7.3 Hz, 2H), 1.91 (d, J=2.5 Hz,2H), 1.99 (s, 2H), 2.10 (m, 2H), 2.31 (td, J=14.0, 3.7 Hz, 2H), 2.91 (s,6H), 2.96 (m, 2H), 3.36 (m, 2H), 3.57 (d, J=12.4 Hz, 2H), 3.63 (br s,1H), 3.84 (s, 2H), 4.29 (t, J=4.0 Hz, 1H), 4.37 (m, 3H), 4.58 (t, J=3.9Hz, 1H), 4.70 (t, J=3.9 Hz, 1H), 6.96 (m, 3H).

EXAMPLE 41

Compound no. 200 was synthesized using known methods and those describedabove.

¹H NMR (400 MHz, CD₃CN) δ 1.72 (d, J=7.2 Hz, 2H), 1.85 (t, J=2.4 Hz,3H), 1.98 (m, 4H), 2.11 (m, 2H), 2.30 (td, J=14.0, 3.6 Hz, 2H), 2.91 (s,6H), 2.96 (br s, 2H), 3.08-3.72 (m, 5H), 3.84 (s, 2H), 4.37 (s, 2H),4.67 (d, J=16.6 Hz, 2H), 6.96 (m, 3H).

EXAMPLE 42

Compound no. 229 was synthesized using known methods and those describedabove.

¹H NMR (400 MHz, CD₃CN) δ 1.66 (br s, 2H), 1.84 (br s, 2H), 1.92 (br s,2H), 1.98 (br s, 2H), 2.23 (m, 3H), 2.50 (dd, J=6.4, 2.5 Hz, 2H), 2.84(s, 6H), 2.93 (m, 2H), 3.08 (m, 2H), 3.50 (d, J=10.9 Hz, 2H), 3.65 (brs, 1H), 3.77 (s, 2H), 4.11 (s, 2H), 4.30 (s, 2H), 6.90 (m, 3H).

EXAMPLE 43

Compound no. 165 was synthesized using known methods and those describedabove.

¹H NMR (400 MHz, DMSO-d₆) d 9.73 (s, 1H), 8.08 (d, J=8.4 Hz, 1H), 7.74(q, J=1.3 Hz, 1H), 7.65 (q, J=2.6 Hz, 1H), 7.60 (dd, J=8.4, 1.7 Hz, 1H),7.49 (dd, J=5.0, 1.2 Hz, 1H), 7.45 (d, J=1.5 Hz, 1H), 4.16-4.10 (m, 4H),4.06 (q, J=7.1 Hz, 2H), 3.56-3.49 (m, 3H), 3.19 (q, J=11.3 Hz, 2H), 2.85(br s, 2H), 2.28-2.23 (m, 5H), 2.10 (d, J=12.9 Hz, 2H), 1.96 (d, J=13.9Hz, 2H), 1.66-1.57 (m, 2H), 1.20 (t, J=7.1 Hz, 3H).

EXAMPLE 44

Compound no. 406 was synthesized using known methods and those describedabove.

¹H NMR (400 MHz, DMSO-d₆) δ 9.62 (s, 1H), 8.03 (d, J=8.3 Hz, 1H), 7.18(d, J=8.4 Hz, 1H), 7.10 (s, 1H), 6.39 (d, J=10.3 Hz, 1H), 5.78-5.69 (m,1H), 4.15-4.10 (m, 4H), 4.06 (q, J=7.1 Hz, 2H), 3.58-3.49 (m, 3H), 3.16(q, J=10.8 Hz, 2H), 2.84 (br s, 2H), 2.21 (s, 3H), 2.16-2.07 (m, 4H),1.93 (d, J=13.9 Hz, 2H), 1.87 (d, J=7.2 Hz, 3H), 1.63-1.55 (m, 2H), 1.20(t, J=7.1 Hz, 3H

EXAMPLE 45

Compound no. 158 was synthesized using known methods and those describedabove.

¹H-NMR (400 MHz, DMSO-d₆) δ 10.40 (br s, 1H), 8.31 (d, J=8.2 Hz, 1H),7.27 (m, 4H), 5.34 (m, 1H), 3.40 (m, 3H), 3.13 (m, 1H), 2.97 (m, 2H),2.65 (m, 1H), 2.57 (br s, 1H), 2.30 (m, 2H), 1.97 (m, 2H), 1.88 (s, 3H),1.65 (m, 4H), 1.46 (m, 5H).

EXAMPLE 46

Compound no. 182 was synthesized using known methods and those describedabove.

¹H-NMR (400 MHz, DMSO-d₆) δ 10.43 (br s, 1H), 8.31 (d, J=8.2 Hz, 1H),7.28 (m, 4H), 5.34 (m, 1H), 3.96 (br m, 2H), 3.59 (s, 3H), 3.50 (m, 2H),3.07 (m, 4H), 2.72 (m, 4H), 2.28 (m, 1H), 2.08 (m, 1H), 1.88 (s, 3H),1.85 (m, 2H), 1.66 (m, 3H), 1.12 (m, 2H).

EXAMPLE 47

Compound no. 358 was synthesized using known methods and those describedabove.

¹H NMR (400 MHz, DMSO-d₆) δ 10.65 (s, 1H), 8.30 (d, J=8.1 Hz, 1H),7.34-7.31 (m, 1H), 7.27 (dt, J=10.1, 3.7 Hz, 1H), 7.22 (d, J=7.3 Hz,1H), 7.17 (d, J=7.3 Hz, 1H), 5.33 (q, J=7.8 Hz, 1H), 4.26 (m, 2H), 4.08(q, J=7.0 Hz, 2H), 3.77-3.70 (m, 1H), 3.52 (t, J=13.0 Hz, 2H), 3.06 (q,J=11.5 Hz, 1H), 2.97 (q, J=11.8 Hz, 1H), 2.61 (dd, J=13.2, 8.0 Hz, 1H),2.54-2.47 (m, 1H), 2.15-2.04 (m, 3H), 1.91-1.81 (m, 7H), 1.71-1.66 (m,5H), 1.22 (t, J=7.1 Hz, 3H).

EXAMPLE 48

Compound no. 191 was synthesized using known methods and those describedabove.

¹H NMR (free base, 400 MHz, DMSO-d₆) δ 10.34 (s, 1H), 7.43 (d, J=7.3 Hz,1H), 7.18 (dt, J=10.6, 3.8 Hz, 1H), 6.94 (dt, J=10.4, 3.8 Hz, 1H), 6.84(d, J=7.6 Hz, 1H), 4.03 (q, J=7.1 Hz, 4H), 2.94-2.88 (m, 2H), 2.79 (s,2H), 2.72-2.66 (m, 2H), 2.58-2.51 (m, 1H), 1.82-1.75 (m, 4H), 1.64-1.59(m, 2H), 1.43-1.33 (m, 2H), 1.18 (t, J=7.1 Hz, 3H).

EXAMPLE 49

Compound no. 199 was synthesized using known methods and those describedabove.

¹H NMR ((free base, 400 MHz, DMSO-d₆) δ 10.35 (s, 1H), 7.42 (d, J=7.4Hz, 1H), 7.17 (dt, J=10.5, 3.8 Hz, 1H), 6.94 (t, J=7.1 Hz, 1H), 6.83 (d,J=7.4 Hz, 1H), 4.18 (m, 2H), 4.05 (q, J=6.5 Hz, 2H), 2.94-2.84 (m, 3H),2.63 (t, J=8.1 Hz, 2H), 1.97-1.83 (m, 3H), 1.78-1.70 (m, 5H), 1.62-1.58(m, 4H), 1.19 (t, J=7.1 Hz, 3H).

EXAMPLE 50

Compound no. 318 was synthesized using known methods and those describedabove. Compound was prepared using reductive amination conditionsdescribed above. ¹H NMR ((free base, 400 MHz, DMSO-d₆) δ 10.35 (s, 1H),7.46 (d, J=7.4 Hz, 1H), 7.18 (dt, J=10.6, 3.8 Hz, 1H), 6.94 (dt, J=10.4,3.8 Hz, 1H), 6.85 (d, J=7.6 Hz, 1H), 4.02 (q, J=7.1 Hz, 2H), 3.97 (m,2H), 2.82-2.77 (m, 4H), 2.56-2.52 (m, 1H), 2.27 (d, J=6.8 Hz, 2H),1.84-1.72 (m, 5H), 1.63-1.59 (m, 2H), 1.18 (t, J=7.1 Hz, 3H), 1.04-0.94(m, 2H).

EXAMPLE 51

Compound no. 104 was synthesized using known methods and those describedabove.

¹H NMR (free base, 400 MHz, DMSO-d₆) δ 7.74-7.68 (m, 2H), 7.61 (d, J=7.6Hz, 1H), 7.46-7.42 (m, 1H), 6.17-6.15 (m, 1H), 5.97-5.95 (m, 1H),2.95-2.76 (m, 4H), 2.55 (s, 2H), 2.36-2.28 (m, 1H), 2.09-1.99 (m, 6H),1.87-1.81 (m, 1H), 1.45 (d, J=3.9 Hz, 2H), 1.34-1.20 (m, 2H), 0.55-0.51(m, 1H)

EXAMPLE 52

Compound no. 186 was synthesized using known methods and those describedabove.

¹H NMR (400 MHz, DMSO-d₆) δ 9.44 (br s, 1H), 7.07-6.95 (m, 2H),6.85-6.82 (m, 1H), (tt, J=28.8, 18.1 Hz, 1H), 4.51 (s, 2H), 4.40-4.31(m, 4H), 3.74 (q, J=5.5 Hz, 1H), 3.59-3.40 (m, 4H), 2.98 (q, J=10.8 Hz,2H), 2.07-1.93 (m, 8H), 1.68 (d, J=5.5 Hz, 4H).

EXAMPLE 53

Compound no. 275 was synthesized using known methods and those describedabove.

¹H NMR (400 MHz, DMSO-d₆) δ 9.25 (br s, 1H), 7.32 (d, J=2.6 Hz, 1H),7.16 (dd, J=8.7, 2.5 Hz, 1H), 6.82 (d, J=8.7 Hz, 1H), 4.11 (t, J=5.1 Hz,2H), 3.38-3.34 (m, 2H), 3.25-3.13 (m, 3H), 2.31-2.23 (m, 2H), 2.08-2.04(m, 4H), 1.85 (d, J=13.7 Hz, 4H), 1.63 (d, J=12.6 Hz, 1H), 1.49-1.39 (m,2H), 1.34-1.29 (m, 2H), 1.21 (m, 1H)

EXAMPLE 54

Compound no. 258 was synthesized using known methods and those describedabove.

¹H NMR (400 MHz, DMSO-d₆) δ 10.60 (s, 1H), 9.20 (bs, 1H), 7.30-7.15 (m,2H), 7.07-6.87 (m, 2H), 3.65-3.35 (m, 5H), 2.66-2.64 (m, 1H), 2.40-2.30(m, 3H), 2.07-1.98 (m, 1H), 1.92 (d, J=14.7 Hz, 1H), 1.79 (d, J=14.3 Hz,1H), 1.68-1.51 (m, 3H), 1.47-1.38 (m, 3H), 1.27-1.20 (m, 1H).

EXAMPLE 55

Compound no. 152 was synthesized using known methods and those describedabove.

¹H NMR (400 MHz, DMSO-d₆) δ 9.41 (br s, 1H), 7.04-6.93 (m, 2H),6.84-6.80 (m, 1H), 4.53 (s, 2H), 3.47 (d, J=12.1 Hz, 1H), 3.40-3.38 (m,1H), 3.24-3.17 (m, 1H), 3.06 (q, J=11.3 Hz, 2H), 2.19-2.11 (m, 2H), 2.05(d, J=10.2 Hz, 2H), 1.94 (d, J=14.1 Hz, 2H), 1.84 (d, J=12.9 Hz, 2H),1.63 (d, J=12.5 Hz, 1H), 1.46-1.23 (m, 4H), 1.17-1.07 (m, 1H).

EXAMPLE 56

Compound no. 288 was synthesized using known methods and those describedabove.

¹H NMR (400 MHz, DMSO-d₆) δ 9.33 (br s, 1H), 7.05-6.92 (m, 2H),6.85-6.80 (m, 1H), 6.34-6.31 (m, 1H), 4.50 (s, 2H), 4.33 (d, J=13.4 Hz,2H), 3.83-3.74 (m, 1H), 3.67-3.51 (m, 3H), 2.95 (q, J=11.0 Hz, 2H),2.07-1.85 (m, 8H), 1.74-1.58 (m, 4H), 1.08 (d, J=6.6 Hz, 6H).

EXAMPLE 57

Compound no. 211 was synthesized using known methods and those describedabove.

¹H NMR (400 MHz, DMSO-d₆) δ 7.65 (br s, 1H), 7.06-6.95 (m, 2H),6.85-6.80 (m, 1H), 5.18 (s, 1H), 4.51 (s, 2H), 4.25 (s, 2H), 3.81-3.71(m, 5H), 3.58 (d, J=12.1 Hz, 2H), 2.98-2.93 (m, 2H), 2.13-1.94 (m, 10H),1.65 (d, J=7.4 Hz, 4H).

EXAMPLE 58

Compound no. 156 was synthesized using known methods and those describedabove.

¹H NMR (400 MHz, DMSO-d₆) δ 9.56 (br s, 1H), 7.06-6.95 (m, 2H),6.86-6.80 (m, 1H), 4.51 (s, 2H), 4.26 (s, 2H), 3.57-3.44 (m, 6H), 2.97(q, J=11.1 Hz, 2H), 2.08-2.02 (m, 4H), 1.94 (d, J=13.5 Hz, 4H),1.70-1.65 (m, 4H).

EXAMPLE 59

Compound no. 181 was synthesized using known methods and those describedabove.

¹H NMR (400 MHz, DMSO-d₆) δ 10.06 (br s, 1H), 7.21 (dd, J=8.5, 2.2 Hz,1H), 7.08 (d, J=2.2 Hz, 1H), 6.85 (d, J=8.5 Hz, 1H), 4.52 (s, 2H),3.47-3.21 (m, 3H), 3.10-2.94 (m, 2H), 2.66-2.40 (m, 3H), 2.27 (s, 1H),1.96-1.83 (m, 4H), 1.56-1.53 (m, 3H), 1.42-1.33 (m, 3H).

EXAMPLE 60

Compound no. 178 was synthesized using known methods and those describedabove.

¹H NMR (400 MHz, DMSO-d₆) δ 9.42 (br s, 1H), 7.30 (d, J=2.6 Hz, 1H),7.18-7.16 (m, 1H), 6.84-6.81 (m, 1H), 4.14-3.99 (m, 2H), 3.46 (d, J=12.1Hz, 4H), 3.36-3.31 (m, 2H), 3.20-3.11 (m, 3H), 2.28-2.20 (m, 2H),2.07-2.00 (m, 4H), 1.88 (d, J=14.4 Hz, 2H), 1.75-1.64 (m, 2H).

EXAMPLE 61 Physical Characteristics of Compounds of Formulae (I and II)

Additional compounds having the structures shown in Table 1 weresynthesized using known methods and those described above.

TABLE 2 Physical Characteristics of Compounds in Table 1 Cmd LCMS LCMSNo. Plus RT 2 327.3 2.8 3 309 1.88 4 379.2 1.99 5 306.2 2.32 6 476.22.34 7 309.4 1.93 8 353.3 2.16 9 426.2 1.94 10 519.4 1.92 11 412.2 1.9812 397.5 2.48 13 328.2 2.05 14 460.5 2.13 15 369.2 2.19 16 508.5 2.2 17458.4 2.35 18 286 2.13 19 378.2 1.94 20 336.4 2.23 21 484.2 2.2 22 459.42.04 23 297.4 1.26 24 524.5 2.44 25 496.5 2.35 26 448.5 2.18 27 359.22.09 28 502.2 2.15 29 367.2 2.31 30 462.4 2.53 31 372.2 1.83 32 477.22.2 33 476.5 2.29 35 357.2 1.99 36 428.2 2.08 37 307.2 1.01 38 464.2 2.139 433.2 2.14 40 546.4 2.53 41 496.4 2.28 42 389.2 2.22 43 411.4 2.31 44496.5 2.31 45 496.4 2.29 46 414.5 2.26 47 472.3 2.08 48 451.2 2.1 49476.2 2.08 50 510.5 2.12 51 365.2 2.11 52 345.2 1.91 53 480.2 2.35 54447.2 2.22 55 381.2 2.21 56 398.2 2.07 57 498.5 2.28 59 514.4 2.2 60418.3 2.22 61 400.5 1.89 62 428.2 2.12 63 476.4 2.63 65 448.2 1.77 66550.4 2.6 67 472.3 2.06 68 395 2.6 69 512.5 2.41 70 387.2 2.02 71 414.21.98 72 325.5 1.94 73 510.3 2.4 74 428.2 2.19 75 347 1.57 76 460.5 2.1177 484.2 2.3 78 476 2.34 79 418.3 2.24 80 532.5 2.33 81 410.3 2.27 82460.5 2.12 83 526.6 2.09 84 480.2 2.28 85 331.3 1.98 87 498.5 2.29 88483.3 2.15 89 547.4 2.49 90 490.4 2.16 91 447.2 2.23 92 400.3 2.16 93544.5 2.29 94 444.5 2.29 95 399.2 2.31 96 488.7 2.25 97 460.5 2.95 98432.5 2.33 99 405.2 2.36 100 467.4 2.41 101 351.2 2.11 102 428.2 2.18103 466.4 2.09 104 308.2 2.08 105 463.4 1.45 106 516.5 2.61 107 377.42.29 108 473.4 2.35 109 384.3 1.72 110 297.5 1.7 111 315.3 1.65 112544.5 2.3 113 390.2 1.76 114 448.4 2.37 115 516.5 2.51 116 397.3 2.59117 520.5 2.33 118 353.4 2.62 120 475.2 2.05 122 492.5 2.53 123 415.22.29 124 443 2.33 125 528.3 2.6 126 462.4 2.23 127 457.4 2.19 128 452.22.06 129 404.5 2.09 130 501.3 2.21 131 373.2 2.31 132 404.4 1.76 133 4292.39 134 399.2 2.02 135 333.2 1.47 136 430.2 2.07 137 414.4 1.99 138339.3 1.97 139 398.2 2.21 140 430.5 2.29 141 420.2 1.95 142 432.4 2.08143 341.2 1.78 144 467.4 1.78 145 448.2 2.36 146 480.2 2.24 148 494.52.56 150 492.4 2.25 151 426.3 2.32 152 290 2.16 153 370.3 1.6 154 419.22.03 155 305.2 1.88 156 375 1.92 157 319.2 2 158 339.3 1.92 159 341.32.96 160 417.5 2.35 161 353.3 2.25 162 532.5 2.33 163 343 2.03 164 3442.56 165 468.2 1.16 166 500.5 2.78 167 446.4 2.12 168 436.2 1.84 169495.4 2.27 170 480.3 2.93 171 339.3 1.92 172 422.2 2 173 420.2 2.07 174456.5 2.4 175 302.3 2.16 176 393.2 2.42 177 540.4 2 178 322.4 2.17 179470.5 2.51 180 351.3 2.22 181 318 2.38 182 400.2 1.86 183 313 1.46 184341.2 1.87 185 351.4 1.86 186 425 2.15 187 331 1.89 188 501.3 2.19 189552.6 2.52 191 358 1.68 192 488.3 2.25 193 492.4 2.25 194 460.4 2.49 195516.5 2.56 196 327.2 1.62 197 525.6 2.44 198 544.5 2.3 199 384.2 2.06200 483.4 2.35 202 432.5 2.31 203 388.2 2.12 204 302.3 2.14 205 412 1.86206 329.5 0.92 207 316.2 2.45 208 406.4 2.29 209 475.2 2.04 210 345.21.94 211 419.4 2.12 212 431.4 1.96 213 351.2 2.11 214 456.5 2.38 215491.2 2.25 216 532.5 2.33 217 410.2 2.26 218 351.2 2.11 219 388.2 2.04220 462.4 2.54 221 504.4 2.14 222 510.4 2.35 223 461.4 2.24 224 317 1.8225 470.5 2.43 226 373 2.23 227 389.2 2.28 228 403.2 1.93 229 446.2 2.21230 483.4 2.3 232 375 2.08 233 552.5 2.25 234 463.2 1.49 235 432.5 2.24236 399.2 2.03 238 308.2 2.09 239 303.3 1.73 240 345.2 2.28 241 NA NA242 313.2 1.88 243 544.5 2.31 244 297.5 1.59 245 426.2 2.05 246 395.22.28 247 431.5 2.46 248 359.2 2.08 249 418.4 1.98 250 414.4 1.91 251357.2 1.99 252 414.5 2.35 253 487.4 2.18 254 444.4 2.23 255 459.4 2.02256 434.4 2.05 257 308.2 2.09 258 409.2 2.68 259 297.2 1.78 260 467.41.74 261 355.4 1.94 262 496.4 2.25 263 294.4 2.33 264 297.4 1.24 265463.2 2.04 266 432.4 2.04 267 484.2 2.27 268 333.5 1.84 269 418.3 2.23270 446.4 2.29 271 424.2 2.38 272 283.3 1.34 273 403.4 2.17 275 383 2.47276 320.2 2.37 278 411.2 2.12 279 442.5 2.08 280 341.2 1.85 281 472.42.44 282 446.4 2.24 283 403.5 2.21 284 434.5 2.05 285 383.2 2.53 286417.5 2.36 287 474.3 2.58 288 336.4 2.17 289 402.4 2.16 290 475.2 1.89291 339.5 0.51 292 392.2 2.13 293 430.5 2.14 294 480.5 2.48 295 530.22.55 296 473.4 2.11 297 516.5 2.65 298 526.6 2.57 299 291 0.45 300 316.21.44 301 426.2 1.98 302 484.5 2.61 303 432.5 2.13 304 532.3 2.31 305351.3 2.22 306 428.5 2.38 307 418.4 1.84 309 418.4 1.9 310 388.5 1.66311 486.5 2.3 313 294 2.33 315 428 1.85 316 428.2 1.95 317 418.6 1.97318 426.3 2.1 319 372.2 1.79 320 403.2 2.23 321 457.2 2.07 322 430.21.94 323 339.1 1.92 324 432.4 2.14 325 289.2 0.77 326 383.2 2.3 327 3861.92 328 331.2 2.11 329 500.3 2.86 330 480.2 2.38 331 467.4 2.01 332397.27 1.79 333 319.2 1.86 334 313 2.01 335 484.2 2.34 336 426 1.96 337353.2 1.84 338 431.4 1.97 339 367.3 2.3 340 416.2 1.76 341 347 2.41 342285.3 1.65 343 316.8 1.64 344 502.4 2.17 345 470.5 2.48 346 458.4 2.35347 397.2 2.47 348 331.3 1.96 349 494.3 2.3 350 297.3 1.04 351 404.5 1.9352 344 0.7 353 457.4 2.22 354 437.2 2.48 355 411.4 2.31 356 417.4 1.94357 403 2.19 358 341.2 1.77 359 426 1.79 360 473.4 2.35 361 516.5 2.5362 459.2 1.96 363 445.3 2.08 364 424 1.8 365 369.2 2.41 366 369.2 2.14367 355.2 2.02 368 401.25 1.75 369 332.2 2.4 370 452.2 2.19 371 430.21.94 372 313.1 1.55 373 487.4 2.19 374 390.3 1.98 375 271.2 0.59 376 3142.39 377 315.3 1.66 378 419.2 1.97 379 482.5 2.55 380 414.5 2.28 381404.4 1.75 382 411.4 2.75 383 452.3 2.17 384 466.4 2.23 385 369 2.19 386460.5 2.51 387 331 1.78 388 508.5 2.21 389 470.5 2.5 390 458.5 2.12 391420.3 2.08 392 351.2 2.11 393 345.2 2.03 394 408.2 1.72 395 432.4 2.01396 502.2 2.34 397 311.3 1.72 398 442.5 2.08 399 428.2 2.06 400 368 1.97401 510.4 2.27 402 516.5 2.51 403 456.5 2.17 404 428.3 2.36 405 504.52.53 406 505.4 1.81 407 426 2.1 408 351.2 2.11 409 486.5 2.7 410 484.22.3 411 552.5 2.25 412 444.4 1.81 413 404.5 2.11 414 357.2 2.39 415322.4 2.15 416 301.2 1.23 417 446.2 2.04 418 446.3 2.02 419 444.5 2.18420 297.5 1.61 421 351.2 2.11 422 504.5 2.51 423 400.5 2.16 424 446.32.01 425 399.2 2.31 426 452.4 2.28 427 434.4 2.21 428 476.2 2.09 429316.2 1.4 430 400.3 1.88

EXAMPLE 62 Assays

Functional Mobilization of Intracellular Calcium to Determine MuscarinicReceptor Activity:

CHO cells expressing muscarinic receptors (M₁ to M₅) are grown asmonolayers in tissue culture flasks at 37° C. in a humidified atmospherecontaining 5% CO₂ and passaged every 3-5 days. The growth media isDulbecco's modified eagles medium (DMEM, Gibco Cat# 12430-054),containing 25 mM Hepes and supplemented with Fetal Bovine Serum(Hyclone, cat# SH30071.03), 0.1 mM of MEM non-essential amino acids(GIBCO, Cat# 11140-050), 1 mM MEM Sodium Pyruvate (GIBCO Cat# 11360-070)and 100 units/ml of Penicillin G and 100 μg/ml of Streptomycin (GIBCOCat# 15140-122). The recombinant muscarinic receptor cell lines aregrown under antibiotic pressure with media containing 25 μg/ml zeocinand 500 μg/ml G418 (M1-CHO), 4 μg/ml puromycin, 50 μg/ml zeocin and 2.5μg/ml blasticidin (M2 and M4-CHO) or 50 μg/ml zeocin and 4 μg/mlpuromycin (M3 and M5-CHO).

Cells are harvested at 80-90% confluence using Versene (GIBCO Cat#15040-066), collected by centrifugation and seeded 18-24 hrs prior torunning the calcium assay at a density of 5,000-10,000 cells/well inback-walled, clear-bottomed 384-well plates (BD Biocoat, poly-D-lysine,Cat#356663). The day of the experiment, the cells are washed with aplate washer (Bioteck Instruments, ELX 405) using bath1 buffer (140-mMNaCl, 4.5-mM KCl, 2-mM CaCl₂, 1-mM MgCl₂, 10-mM Hepes-Na, 10-mM Glucose,pH 7.4, with NaOH) containing 1 mM Probenecid. Next, the calcium dyeFluo-3 (25 μl/well of Fluo-3 AM at 4 μM, Molecular Probes F-1241, inBath 1 buffer containing 1 mM Probenecid) is added to the 25 μl of Bath1 remaining in each well after the plate wash and the dye is loaded at37° C. in the tissue culture incubator for 60-90 min. The fluorescentdye is removed using the plate washer with Bath 1 containing 1 mMProbenecid, leaving 25 μl/well of this solution after the wash.Alternatively, cells can be loaded with the calcium indicator fromMolecular Devices (Calcium 3 Assay Reagents, Cat # R7181) adding 5 μl ofa 5× solution dye in Bath 1 containing 1 mM Probenecid (10 ml per dyeflask cat# R7182 to generate a solution 20×) to 20 μl of the samebuffer. After loading for 60 min, the experiment can be run withouthaving to remove the dye.

Compounds are prepared at a 2× fold concentration in a 96-well plate(round bottom, Costar Corning cat# 3656), by reconstituting thepre-spotted compounds in bath 1 containing 1 mM probenecid. The finalconcentration DMSO is 0.5%, and the amount of DMSO is normalized acrossthe assay plate. To determine an agonist action of the compounds onmuscarinic receptors, the reconstituted compounds are added (25 μlcompound/well) to the cell assay plate (containing 25 μl/well) using themulti-channel robotic system of the FLIPR 3 Instrument (MolecularDevices, Sunnyvale, Calif.). To determine a functional inhibitory actionof the compounds on muscarinic receptors, the reconstituted compoundsare added (25 μl compound/well) to the assay plate and pre-incubated for15 min prior to adding 25 μl of Carbachol at 3× the EC80 for eachmuscarinic subtype. Alternatively, the compounds can be co-appliedsimultaneously with the agonist. In both assay modes, the fluorescenceis recorded for 60 sec (excitation wavelength is 488 nM and emissionwavelength 540 nm) using the FLIPR 3 instrument.

The potency, efficacy and selectivity of the muscarinic compounds wereevaluated by screening the compound activity across the whole family (M₁to M₅ cells). Compounds were also screened for activity on otherproteins such as other GPCRs and ion channels to determine selectivityon M4 receptors.

The compounds of the present invention were found to modulate the M₁and/or M₄ muscarinic receptors selectively over the other receptortypes.

Examples of activities and efficacies of the muscarinic compounds offormulae (I and II) on modulating M₁ and M₄ receptors are shown below inTable 2. The compound activity for the M₁ and M₄ receptor is illustratedwith “xxx” if activity was measured to be less than 0.1 μM, “xx” ifactivity was measured to be between 0.1 μM and 1.0 μM, and “x” ifactivity was measured to be greater than 1.0 μM. The efficacy for M₁ andM₄ modulation is illustrated with “xxx” if efficacy was calculated to begreater than 85%, “xx” if efficacy was calculated to be between 85% and65%, and “x” if efficacy was calculated to be less than 65%.

TABLE 2 Compound activities and efficacies for modulating M₁ and M₄receptors Cmd M₁ M₄ M₁ M₄ No. Activity Activity Efficacy Efficacy 1 + ++++ +++ 2 + + ++ + 3 + ++ ++ ++ 4 + ++ ++ + 5 ++ ++ ++ ++ 6 + + + + 7 + +++ ++ 8 + ++ ++ + 9 +++ ++ +++ ++ 10 + + ++ + 11 +++ +++ ++ ++ 12 + + ++++ 13 ++ ++ + + 14 + + + + 15 ++ ++ ++ + 16 ++ ++ ++ + 17 + + +++ +18 + + + + 19 +++ +++ +++ ++ 20 + + + + 21 ++ ++ ++ ++ 22 ++ ++ ++ ++23 + ++ ++ ++ 24 ++ ++ ++ ++ 25 ++ ++ ++ ++ 26 + + ++ ++ 27 + + ++ + 28++ +++ +++ ++ 29 + ++ + + 30 + + ++ ++ 31 ++ ++ +++ +++ 32 ++ ++ ++ ++33 ++ ++ ++ ++ 34 +++ +++ ++ ++ 35 + ++ ++ ++ 36 + + + + 37 + + ++ ++ 38++ ++ +++ +++ 39 +++ +++ ++ ++ 40 ++ ++ ++ ++ 41 + + ++ + 42 +++ +++ +++++ 43 ++ ++ ++ + 44 ++ ++ ++ ++ 45 + ++ ++ ++ 46 ++ +++ ++ +++ 47 ++ ++++ + 48 ++ ++ ++ +++ 49 ++ ++ ++ ++ 50 +++ +++ +++ ++ 51 + + + + 52 + +++ ++ 53 + + ++ + 54 ++ ++ ++ ++ 55 + + + + 56 +++ +++ +++ ++ 57 + +++ + 58 + + ++ ++ 59 + + + + 60 +++ +++ +++ +++ 61 +++ ++ +++ + 62 ++ +++ + 63 + + ++ + 64 ++ + ++ + 65 + + ++ + 66 + + ++ + 67 ++ ++ ++ + 68++ ++ + + 69 ++ ++ ++ + 70 ++ +++ ++ ++ 71 + ++ ++ ++ 72 + + + + 73 ++++ + + 74 +++ ++ +++ ++ 75 + + + + 76 ++ ++ ++ + 77 + + ++ + 78 + + ++ +79 ++ ++ ++ + 80 ++ ++ ++ ++ 81 ++ +++ ++ ++ 82 + + + + 83 + ++ ++ ++84 + + ++ + 85 ++ ++ ++ ++ 86 +++ ++ +++ ++ 87 ++ ++ ++ + 88 ++ ++ +++++ 89 ++ ++ ++ ++ 90 ++ +++ ++ ++ 91 ++ ++ ++ ++ 92 +++ ++ ++ ++ 93 ++++ ++ ++ 94 ++ ++ ++ + 95 ++ ++ ++ + 96 ++ ++ ++ + 97 ++ ++ ++ +98 + + + + 99 +++ +++ +++ ++ 100 + + + + 101 + ++ ++ + 102 ++ ++ +++ +++103 +++ +++ ++ ++ 104 ++ ++ ++ ++ 105 + + ++ ++ 106 + ++ ++ + 107 ++++++ +++ +++ 108 ++ ++ ++ ++ 109 +++ +++ +++ ++ 110 + ++ ++ ++ 111 + ++++ ++ 112 ++ ++ ++ + 113 + + + + 114 + + +++ ++ 115 ++ ++ ++ ++ 116 + ++++ + 117 ++ ++ ++ ++ 118 ++ ++ ++ ++ 119 ++ ++ ++ ++ 120 + + ++ + 122++ ++ ++ + 123 +++ + + + 124 +++ ++ ++ + 125 + ++ ++ + 126 + + ++ ++ 127++ ++ ++ ++ 128 ++ + ++ +++ 129 ++ ++ ++ ++ 130 ++ ++ ++ ++ 131 ++ ++++ + 132 ++ + +++ ++ 133 ++ + + + 134 + + + + 135 + + + + 136 ++ + ++ +137 +++ ++ ++ ++ 138 + + ++ + 139 ++ ++ ++ ++ 140 ++ + + + 141 +++ +++++ ++ 142 ++ ++ ++ ++ 143 + ++ ++ + 144 + + +++ ++ 145 ++ + ++ ++146 + + ++ ++ 147 ++ ++ ++ ++ 148 + + + + 149 +++ +++ +++ ++ 150 + +++ + 151 ++ + + + 152 ++ ++ ++ ++ 153 +++ ++ +++ ++ 154 ++ ++ +++ +++155 ++ ++ ++ ++ 156 ++ ++ ++ ++ 157 + ++ + ++ 158 + ++ ++ +++ 159 +++ + + 160 + + + + 161 ++ +++ ++ ++ 162 ++ ++ ++ ++ 163 + + + + 164 + +++ + 165 + + ++ ++ 166 + ++ ++ + 167 +++ +++ +++ ++ 168 ++ ++ ++ ++ 169++ + +++ + 170 ++ ++ ++ + 171 + + + + 172 ++ + +++ ++ 173 ++ ++ +++ ++174 ++ + ++ + 175 + + ++ ++ 176 ++ +++ +++ +++ 177 + + ++ ++ 178 ++ + ++++ 179 ++ ++ ++ ++ 180 + ++ + ++ 181 ++ + ++ ++ 182 ++ +++ ++ +++ 183 ++++ ++ ++ 184 + ++ ++ ++ 185 ++ +++ ++ ++ 186 +++ +++ ++ + 187 + + + +188 ++ ++ ++ ++ 189 ++ ++ ++ ++ 190 ++ +++ ++ ++ 191 ++ ++ ++ ++ 192 ++++ ++ + 193 + + +++ ++ 194 + + ++ + 195 ++ ++ ++ + 196 + + ++ + 197 ++++ +++ ++ 198 ++ ++ ++ ++ 199 +++ ++ +++ ++ 200 +++ +++ +++ +++ 202 ++++ ++ + 203 + + + + 204 + ++ ++ ++ 205 ++ ++ ++ ++ 206 + + ++ + 207 ++++ ++ ++ 208 + + ++ ++ 209 + + ++ + 210 + ++ ++ ++ 211 + + ++ + 212 ++++ ++ + 213 ++ +++ ++ ++ 214 ++ ++ ++ ++ 215 + + ++ ++ 216 ++ ++ ++ ++217 ++ ++ ++ + 218 ++ +++ ++ ++ 219 ++ ++ ++ ++ 220 + + ++ ++ 221 + ++++ ++ 222 + ++ ++ ++ 223 ++ ++ ++ ++ 224 + ++ ++ +++ 225 +++ ++ ++ ++226 + + + + 227 ++ +++ ++ ++ 228 ++ + +++ + 229 +++ +++ +++ +++ 230 ++++ ++ ++ 231 + + + + 232 + + ++ ++ 233 ++ + ++ + 234 + + + + 235 ++ ++++ + 236 + + + + 237 ++ ++ ++ +++ 238 ++ + ++ + 239 + + + + 240 + + ++ +241 + ++ + + 242 + + ++ ++ 243 ++ ++ ++ + 244 + + ++ ++ 245 ++ ++ ++ +++246 + ++ + + 247 + + + + 248 + + + + 249 +++ +++ +++ +++ 250 +++ +++ ++++++ 251 + ++ ++ + 252 ++ + ++ + 253 + + ++ ++ 254 ++ ++ ++ ++ 255 ++ +++++ ++ 256 ++ ++ ++ ++ 257 + + ++ ++ 258 ++ + + + 259 + + ++ ++ 260 + ++++ ++ 261 + ++ + + 262 + + ++ ++ 263 ++ ++ ++ ++ 264 + + ++ ++ 265 ++++ ++ ++ 266 ++ + ++ + 267 + + ++ ++ 268 + + + + 269 ++ ++ ++ + 270 ++++ +++ ++ 271 ++ ++ ++ + 272 + + ++ ++ 273 + + + + 274 + + ++ ++ 275 ++++ ++ + 276 ++ ++ ++ ++ 277 + + + + 278 +++ ++ ++ + 279 + + + + 280 + +++ + 281 + + ++ + 282 + + ++ + 283 ++ ++ ++ + 284 ++ ++ ++ + 285 + ++++ + 286 ++ ++ ++ + 287 + + + + 288 + + + + 289 ++ ++ ++ + 290 ++ + +++++ 291 + ++ ++ ++ 292 + + + + 293 ++ ++ ++ + 294 ++ ++ ++ ++ 295 + + ++++ 296 ++ ++ ++ +++ 297 ++ ++ ++ ++ 298 + ++ ++ + 299 + + ++ ++ 300 + +++ + 301 ++ ++ ++ ++ 302 + ++ ++ + 303 +++ +++ +++ +++ 304 ++ ++ ++ +305 ++ +++ ++ ++ 306 + + + + 307 ++ ++ +++ +++ 308 ++ ++ ++ ++ 309 ++ +++++ +++ 310 +++ +++ +++ ++ 311 + ++ ++ + 312 ++ ++ ++ ++ 313 + + + +314 + ++ +++ +++ 315 +++ +++ ++ +++ 316 +++ +++ ++ ++ 317 ++ ++ +++ ++318 +++ ++ +++ ++ 319 ++ +++ +++ +++ 320 ++ + ++ + 321 ++ + +++ ++322 + + ++ ++ 323 + + + + 324 ++ ++ ++ + 325 ++ +++ ++ ++ 326 ++ ++ ++++ 327 ++ ++ +++ +++ 328 ++ ++ ++ + 329 + + ++ ++ 330 + + ++ + 331 ++ +++++ ++ 332 ++ ++ ++ ++ 333 ++ +++ ++ ++ 334 ++ + ++ + 335 ++ + ++ + 336++ ++ ++ + 337 ++ ++ ++ ++ 338 ++ + ++ + 339 ++ +++ + + 340 ++ ++ ++ ++341 ++ + +++ + 342 + + ++ + 343 + + + + 344 ++ ++ ++ ++ 345 ++ ++ ++ +346 ++ ++ ++ ++ 347 + ++ ++ + 348 + ++ ++ ++ 349 ++ ++ ++ ++ 350 + ++ ++++ 351 +++ +++ +++ ++ 352 ++ ++ +++ ++ 353 ++ +++ ++ +++ 354 + + ++ +355 ++ ++ ++ + 356 +++ +++ +++ +++ 357 ++ +++ ++ +++ 358 + + + + 359 ++++++ ++ ++ 360 ++ ++ ++ ++ 361 ++ ++ ++ ++ 362 +++ +++ +++ ++ 363 ++++ + + 364 +++ +++ ++ +++ 365 +++ +++ ++ ++ 366 + + + + 367 ++ ++ + +368 +++ +++ +++ ++ 369 ++ + ++ ++ 370 ++ ++ ++ + 371 +++ +++ +++ ++372 + + + + 373 + + ++ + 374 ++ ++ ++ ++ 375 + + ++ ++ 376 ++ +++ ++ ++377 ++ ++ ++ ++ 378 ++ ++ ++ + 379 ++ ++ ++ + 380 ++ ++ ++ + 381 + + ++++ 382 + + ++ + 383 ++ ++ ++ + 384 + + ++ + 385 ++ ++ ++ ++ 386 ++ ++++ + 387 + + ++ ++ 388 ++ ++ ++ + 389 ++ ++ ++ + 390 ++ ++ ++ ++ 391 ++++++ +++ ++ 392 + ++ ++ ++ 393 + + + + 394 + + + + 395 ++ + ++ + 396 + ++++ ++ 397 + ++ ++ ++ 398 ++ + + + 399 ++ ++ + + 400 + + + + 401 + + +++++ 402 ++ ++ ++ + 403 + + + + 404 + + + + 405 ++ ++ ++ ++ 406 + + ++ +407 ++ ++ +++ +++ 408 + + + + 409 ++ ++ +++ ++ 410 + + ++ + 411 ++ ++ +++

Other Embodiments

It is to be understood that while the invention has been described inconjunction with the detailed description thereof, the foregoingdescription is intended to illustrate and not limit the scope of theinvention, which is defined by the scope of the appended claims. Otheraspects, advantages, and modifications are within the scope of thefollowing claims.

1. A compound formula (I)

or pharmaceutically acceptable salts thereof, wherein Each of R₁, R₂, R₃is independently Q₁ or Q₂, or R₂ and R₃ together form oxo; Z₁ is —N(Q₁)-or —N(Q₂)-; Z₂ is N; L is a bond, an aliphatic group, C₃-C₆cycloaliphatic, —O—, —S(O)_(z)—, —S(O)_(z)—(C₁-C₄)alkyl-, or —S(O)_(z)N(Q₂)-, in which the aliphatic group is optionally substituted with Q₁,or Q₂; G is a monocycloheteroaliphatic group containing at least one Natom, adamantyl, or a bicyclic or a tricyclic group of the formula (III)

wherein the monocycloheteroalipahtic group, the adamantyl, and thebicyclic or tricyclic group are connected to L via any ring atomincluding those in X₁ and ring B, and the monocycloheteroaliphatic, thebicyclic, and the tricyclic groups are optionally substituted with 1-3of oxo, ═N—OQ₄, fluorine, Q₂, —C(O)—X₂-aliphatic in which X₂ is absent,—O—, —NH—, —NQ₂-, or —S(O)_(z)— and the aliphatic group is optionallysubstituted with 1-3 substituents independently selected from Q₃; Bond ris a single or double bond and when ring B is present, bond r is fusedwith B; Ring B, when present, is a 5-6 membered cycloaliphatic orheterocycloaliphatic ring, and is optionally substituted with 1-3 ofoxo, Q₁, or Q₂; X₁ is —(CH₂)_(i)—, —O—, —S—, —N(Q₂)-, or—N(C(O)—X₂-aliphatic) in which X₂ is absent, —O—, —NH—, —NQ₂-, or—S(O)_(z)— and the aliphatic group is optionally substituted with 1-3substituents independently selected from Q₃; Each Q₁ is independentlyhalo, —CN, —NO₂, —OQ₂, —S(O)_(z)Q₂, —S(O)_(z)N(Q₂)₂, —N(Q₂)₂, —C(O)OQ₂,—C(O)-Q₂, —C(O)N(Q₂)₂, —C(O)N(Q₂)(OQ₂) —N(Q₂)C(O)-Q₂, —N(Q₂)C(O)N(Q₂)₂,—N(Q₂)C(O)O-Q₂, —N(Q₂)S(O)_(z)-Q₂ or aliphatic optionally including 1-3substituents independently selected from Q₂ or Q₃; Each Q₂ isindependently H, aliphatic, cycloaliphatic, aryl, arylalkyl,heterocyclic, or heteroaryl ring, each optionally including 1-3substituents independently selected from Q₃; Each Q₃ is halo, oxo, —CN,—NO₂, —CF₃, —OCF₃, —OH, —S(O)_(z)Q₄, —N(Q₄)₂, —COOQ₄, —C(O)Q₄, —OQ₄, orC₁-C₄ alkyl optionally substituted with halo, oxo, —CN, —NO₂, —CF₃,—OCF₃, —OH, —SH, —S(O)_(z)H, —NH₂, or —COOH; Each Q₄ is aliphatic,cycloaliphatic, aryl, aralkyl, heterocycloaliphatic, heteroaralky, orheteroaryl, each optionally including 1-3 substituents selected fromhalo, oxo, CN, NO₂, CF₃, OCF₃, OH, SH, —S(O)_(z)H, —NH₂, or COOH; EachQ₅ is a heterocyclic ring optionally including 1-3 substituents selectedfrom halo, C₁-C₄alkyl, oxo, CN, NO₂, CF₃, OCF₃, OH, SH, —S(O)_(z)H,—NH₂, COOH; Each i is independently 1, 2, or 3; Each m and n is 2; Eachp is 0; Each y is independently 0 or 1; Each z is independently 0, 1, or2; Each t is 1 to 4; and Provided that when L is —C(O)—CH₂— and Z₁ is—N(Q₁)-, where Q₁ is —S(O)₂-optionally substituted phenyl; the R₁substituent is other than H; L is —S(O)₂—(C₁-C₄alkyl-, and R₂ and R₃form ═O, and Z₁ is —N(Q₁)-, where Q₁ is aliphatic or —S(O)₂-aliphatic;the R₁ substituent is other than H; and L is aliphatic, and R₂ and R₃form ═O, and Z₁ is —N(Q₁)-, where Q₁ is aliphatic, and G is asubstituted monocycloheteroaliphatic group; the R₁ substituent is otherthan H.
 2. The compound of claim 1, wherein G is optionally substitutedwith Q₂, or —C(O)—X₂-aliphatic, where X₂ is absent, —O—, —NH—, or —NQ₂-,and the aliphatic group is optionally substituted with 1-3 substituentsindependently selected from Q₃.
 3. The compound of claim 1, wherein G issubstituted with alkyl, aryl, haloalkyl, alkoxycarbonyl, or alkoxyamino.4. The compound of claim 1, wherein G is an optionally substituted 5 to7 membered monoheterocycloaliphatic group.
 5. The compound of claim 4,wherein G includes at least one N atom.
 6. The compound of claim 5,wherein G is substituted with 1 to 2 substituents independently selectedfrom Q₂, and —C(O)—X₂-aliphatic, where X₂ is absent, —O—, —NH—, or—NQ₂-, and the aliphatic group is optionally substituted with 1-3substituents independently selected from Q₃.
 7. The compound of claim 6,wherein G is substituted with 1 to 2 substituents independently selectedfrom alkoxycarbonyl, alkynyloxycarbonyl, alkoxyalkoxycarborayl,haloalkoxycarbonyl, heterocycloalkoxycarbonyl, and cycloalkoxycarbonyl.8. The compound of claim 1, wherein G is selected from


9. The compound of claim 1, wherein G is an optionally substitutedbicyclic group of formula (III) in which ring B is absent.
 10. Thecompound of claim 9, wherein X₁ is —(CH₂)_(i)—.
 11. The compound ofclaim 9, wherein G is optionally substituted bicyclo[2.2.1]heptyl,bicyclo[3.2.1]octyl, bicyclo[3.3.1]nonyl, bicyclo[2.2.2]octyl, orbicyclo[2.2.1]heptanyl.
 12. The compound of claim 11, wherein G issubstituted with 1 to 2 substituents independently selected from Q₂, and—C(O)—X₂-aliphatic, where X₂ is absent, —O—, —NH—, or —NQ₂-, and thealiphatic group is optionally substituted with 1-3 substituentsindependently selected from Q₃.
 13. The compound of claim 10, wherein X₁is —N(Q₂)- or —N(C(O)—X₂-aliphatic, where X₂ is absent, —O—, —NH—, or—NQ₂-, and the aliphatic group is optionally substituted with 1-3substituents independently selected from Q₃.
 14. The compound of claim13, wherein G is an optionally substituted tropane.
 15. The compound ofclaim 14, wherein the tropane is substituted with Q₂, and —C(O)—X₂-aliphatic, where X₂ is absent, —O—, —NH—, or —NQ₂-, and thealiphatic group is optionally substituted with 1-3 substituentsindependently selected from Q₃.
 16. The compound of claim 15, whereinthe tropane is substituted at the tropane ring nitrogen atom withalkoxycarbonyl, alkoxyalkoxycarbonyl, heterocycloalkoxycarbonyl,cycloalkoxycarbonyl, alkoxyaryloxycarbonyl, alkylaminocarbonyl,haloalkoxycarbonyl, alkynyloxycarbonyl, orheterocycloalkylalkoxycarbonyl.
 17. The compound of claim 16, wherein Gis selected from


18. The compound of claim 1, wherein Z₁ is —N(Q₁)-.
 19. The compound ofclaim 18, wherein Z₁ is —N(Q₁)- and Q₁ is alkylcarbonylamino,alkylsulfonylaxnino, alkoxycarbonylamino, aminocarbonyl,alkylcarbonylalkyl, alkoxyalkoxycarbonyl, alkoxyallcyl,alkylaminocarbonyl, alkoxycarbonyl, haloarylcarbonyl, haloarylsulfonyl,alkylheteroarylcarbonyl, heteroarylcarbonyl, heterocycloalkylcarbonyl,haloarylaminocarbonyl, allcylheteroarylsulfonyl, cyanoalkylarylcarbonyl,heterocycloalkoxycarbonyl, alkynyloxycarbonyl, cycloalkoxycarbonyl,heterobicycloarylcarbonyl, alkylheteroarylaminocarbonyl, alkylsulfonyl,alkylcarbonylalkyl, alkoxyarylcarbonyl, haloalkoxycarbonyl,alkylarylcarbonyl, haloalkoxyarylcarbonyl, or arylaminocarbonyl.
 20. Thecompound of claim 1, wherein Z₁ is —NH—,


21. The compound of claim 1, wherein R₁ is selected from hydrogen, halo,or optionally substituted alkyl, heteroaryl, alkoxy, alkenyl,cycloalkyl, cyanoalkylaryl, alkylaryl, alkylsulfonylaryl,alkylcarbonylaryl, aryl, aminocarbonylaryl, alkylcarbonylaminoaryl,cycloalkenyl, and alkoxyaryl.
 22. The compound of claim 21, wherein R₁is selected from hydrogen, halo, methyl,


23. The compound of claim 1, wherein R₂ and R₃ are independentlyhydrogen, alkyl, or R₂ and R₃ together form an oxo.
 24. The compound ofclaim 23, wherein R₂ and R₃ are both hydrogen.
 25. The compound of claim1, wherein L is a bond or an aliphatic group optionally substituted withQ₁, or Q₂.
 26. The compound of claim 25, wherein L is a bond.
 27. Thecompound of claim 25, wherein L is —CH₂—.
 28. The compound of claim 1,wherein the compound is selected from


29. A pharmaceutical composition comprising a compound according toclaim 1 and a pharmaceutical carrier.
 30. A compound formula (I)

or pharmaceutically acceptable salts thereof, wherein Each of R₁, R₂, R₃is independently Q₁ or Q₂, or R₂ and R₃ together form oxo; Z₁ is —N(Q₁)-or —N(Q₂)-; Z₂ is N; L is a bond, or a —CH₂—, G is amonocycloheteroaliphatic group containing at least one N atom,adamantyl, or a bicyclic or a tricyclic group of the formula (III)

wherein the monocycloheteroalipahtic group the adamantyl, and thebicyclic or tricyclic group are connected to L via any ring atomincluding those in X₁ and ring B, and the monocycloheteroaliphatic, thebicyclic, and the tricyclic groups are optionally substituted with 1-3of oxo, ═N—OQ₄, fluorine, Q₂, —C(O)—X₂-aliphatic in which X₂ is absent,—O—, —NH—, —NQ₂-, or —S(O)₂— and the aliphatic group is optionallysubstituted with 1-3 substituents independently selected from Q₃; Bond ris a single or double bond and when ring B is present, bond r is fusedwith B; Ring B, when present, is a 5-6 membered cycloaliphatic orheterocycloaliphatic ring, and is optionally substituted with 1-3 ofoxo, Q₁, or Q₂; X₁ is —(CH₂)_(i)—, —O—, —S—, —N(Q₂)-, or—N(C(O)—X₂-aliphatic) in which X₂ is absent, —O—, —NH—, —NQ₂-, or—S(O)_(z)— and the aliphatic group is optionally substituted with 1-3substituents independently selected from Q₃; Each Q₁ is independentlyhalo, —CN, —NO₂, —OQ₂, —S(O)_(z)Q₂, —S(O)_(z)N(Q₂)₂, —N(Q₂)₂, —C(O)OQ₂,—C(O)-Q₂, —C(O)N(Q₂)₂, —C(O)N(Q₂)(OQ₂), —N(Q₂)C(O)-Q₂, —N(Q₂)C(O)N(Q₂)₂,—N(Q₂)C(O)O-Q₂, —N(Q₂)S(O)_(z)-Q₂ or aliphatic optionally including 1-3substituents independently selected from Q₂ or Q₃; Each Q₂ isindependently H, aliphatic, cycloaliphatic, aryl, arylalkyl,heterocyclic, or heteroaryl ring, each optionally including 1-3substituents independently selected from Q₃; Each Q₃ is halo, oxo, —CN,—NO₂, —CF₃, —OCF₃, —OH, —S(O)_(z)Q₄, —N(Q₄)₂, —COOQ₄, —C(O)Q₄, —OQ₄, orC₁-C₄ alkyl optionally substituted with halo, oxo, —CN, —NO₂, —CF₃,—OCF₃, —OH, —SH, —S(O)_(z)H, —NH₂, or —COOH; Each Q₄ is aliphatic,cycloaliphatic, aryl, aralkyl, heterocycloaliphatic, heteroaralky, orheteroaryl, each optionally including 1-3 substituents selected fromhalo, oxo, CN, NO₂, CF₃, OCF₃, OH, SH, —S(O)_(z)H, —NH₂, or COOH; EachQ₅ is a heterocyclic ring optionally including 1-3 substituents selectedfrom halo, C₁-C₄alkyl, oxo, CN, NO₂, CF₃, OCF₃, OH, SH, —S(O)_(z)H,—NH₂, COOH; Each i is independently 1, 2, or 3; Each m and n is 2; Eachp is 0; Each y is independently 0 or 1; Each z is independently 0, 1, or2; Each t is 1 to 4; and Provided that when L is aliphatic, and R₂ andR₃ form ═O, and Z₁ is —N(Q₁)—, where Q₁ is aliphatic, and G is asubstituted monocycloheteroaliphatic group; the R₁, substituent is otherthan H.
 31. The compound of claim 30 wherein L is —CH₂—.